Fluvastatin Converts Human Macrophages into Foam Cells with Increased Inflammatory Response to Inactivated Mycobacterium tuberculosis H37Ra.

Cholesterol biosynthesis inhibitors (statins) protect hypercholesterolemic patients against developing active tuberculosis, suggesting that these drugs could help the host to control the pathogen at the initial stages of the disease. This work studies the effect of fluvastatin on the early response of healthy peripheral blood mononuclear cells (PBMCs) to inactivated Mycobacterium tuberculosis (Mtb) H37Ra. We found that in fluvastatin-treated PBMCs, most monocytes/macrophages became foamy cells that overproduced NLRP3 inflammasome components in the absence of immune stimulation, evidencing important cholesterol metabolism/immunity connections. When both fluvastatin-treated and untreated PBMCs were exposed to Mtb H37Ra, a small subset of macrophages captured large amounts of bacilli and died, concentrating the bacteria in necrotic areas. In fluvastatin-untreated cultures, most of the remaining macrophages became epithelioid cells that isolated these areas of cell death in granulomatous structures that barely produced IFNγ. By contrast, in fluvastatin-treated cultures, foamy macrophages surrounded the accumulated bacteria, degraded them, markedly activated caspase-1 and elicited a potent IFNγ/cytotoxic response. In rabbits immunized with the same bacteria, fluvastatin increased the tuberculin test response. We conclude that statins may enhance macrophage efficacy to control Mtb, with the help of adaptive immunity, offering a promising tool in the design of alternative therapies to fight tuberculosis.

5-HT2A Receptor Knockout Mice Show Sex-Dependent Differences following Acute Noribogaine Administration.

Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga. The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT2A receptor (5-HT2AR) in mice. In that regard, we used male and female, 5-HT2AR knockout (KO) and wild type (WT) mice injected with a single noribo dose (10 or 40 mg/kg; i.p.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT2AR levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT2AR mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT2AR blunted noribo-mediated responses to NMDA synaptic transmission.

Biochars from Olive Stones as Carbonaceous Support in Pt/TiO2-Carbon Photocatalysts and Application in Hydrogen Production from Aqueous Glycerol Photoreforming.

Several biochars were synthesized from olive stones and used as supports for TiO2, as an active semiconductor, and Pt as a co-catalyst (Pt/TiO2-PyCF and Pt/TiO2-AC). A third carbon-supported photocatalyst was prepared from commercial mesoporous carbon (Pt/TiO2-MCF). Moreover, a Pt/TiO2 solid based on Evonik P25 was used as a reference. The biochars used as supports transferred, to a large extent, their physical and chemical properties to the final photocatalysts. The synthesized catalysts were tested for hydrogen production from aqueous glycerol photoreforming. The results indicated that a mesoporous nature and small particle size of the photocatalyst lead to better H2 production. The analysis of the operational reaction conditions revealed that the H2 evolution rate was not proportional to the mass of the photocatalyst used, since, at high photocatalyst loading, the hydrogen production decreased because of the light scattering and reflection phenomena that caused a reduction in the light penetration depth. When expressed per gram of TiO2, the activity of Pt/TiO2-PyCF is almost 4-times higher than that of Pt/TiO2 (1079 and 273 mmol H2/gTiO2, respectively), which points to the positive effect of an adequate dispersion of a TiO2 phase on a carbonaceous support, forming a highly dispersed and homogeneously distributed titanium dioxide phase. Throughout a 12 h reaction period, the H2 production rate progressively decreases, while the CO2 production rate increases continuously. This behavior is compatible with an initial period when glycerol dehydrogenation to glyceraldehyde and/or dihydroxyacetone and hydrogen predominates, followed by a period in which comparatively slower C-C cleavage reactions begin to occur, thus generating both H2 and CO2.

Aversive memory conditioning induces fluoxetine-dependent anxiety-like states in the crab Neohelice granulata.

The interactions between memory processes and emotions are complex. Our previous investigations in the crab Neohelice led to an adaptation of the affective extension of sometimes opponent processes (AESOP) model. The model proposes that emotions generate separate emotive memory traces, and that the unfolding of emotional responses is a crucial component of the behavioral expression of reactivated memories. Here, we show that an aversive conditioning, that used changes in an innate escape response to an aversive visual stimulus, induced an emotional behavior that endured beyond the stimuli: the aversive memory training built an anxiety-like state evaluated in a dark/light plus-maze. We found that, after the training session, crabs displayed aversion to maze light areas, and an increased time immobilized in the dark zones of the maze, an anxiety-like behavior induced by stressors or physiological conditions in other crustaceans. The training-dependent anxiety-like behavior was blocked by pretraining administration of fluoxetine, suggesting an underlying serotonin-dependent phenomenon. We hypothesize that this training-induced anxiety-like state generates a separate emotive memory trace that is reinstated and crucial for the modulation of memory expression once the memory is reactivated.

Synthesis of Fe-TiO2 and Cu-TiO2 Based Materials by Olive Leaves Biotemplating-Application to Hydrogen Production from Glycerol Photoreforming.

Hydrogen production is mainly based on the use of fossil fuels, but currently, many alternative routes are being developed, among which the photo-reforming of oxygenated organic compounds stands out. Recently, several studies have been carried out in order to develop new techniques to create bio-inspired TiO2 structures. One of these is 'biotemplating', a process that replicates a biological system in an inorganic TiO2-based structure. In this study, olive by-products-olive leaves-are valorized as a biotemplate for the synthesis of new Fe-TiO2- and Cu-TiO2-based photocatalysts with the aim of improving the replication of the leaf structure and enhancing hydrogen photoproduction. In conclusion, the incorporation of iron and copper decreases the band gap and increases the energetic disorder at the band edges. Moreover, it is verified by SEM and TEM that the metals are not found forming particles but are introduced into the formed TiO2 structure. The accuracy of the internal and external structure replication is improved with the incorporation of Fe in the synthesis, while the incorporation of Cu substantially improves the production of hydrogen, which is multiplied 14 times under UV light and 6 times under sunlight, as compared to a pure TiO2 structure.

Redundancy Analysis to Reduce the High-Dimensional Near-Infrared Spectral Information to Improve the Authentication of Olive Oil.

The high price of marketing of extra virgin olive oil (EVOO) requires the introduction of cost-effective and sustainable procedures that facilitate its authentication, avoiding fraud in the sector. Contrary to classical techniques (such as chromatography), near-infrared (NIR) spectroscopy does not need derivatization of the sample with proper integration of separated peaks and is more reliable, rapid, and cost-effective. In this work, principal component analysis (PCA) and then redundancy analysis (RDA)─which can be seen as a constrained version of PCA─are used to summarize the high-dimensional NIR spectral information. Then PCA and RDA factors are contemplated as explanatory variables in models to authenticate oils from qualitative or quantitative analysis, in particular, in the prediction of the percentage of EVOO in blended oils or in the classification of EVOO or other vegetable oils (sunflower, hazelnut, corn, or linseed oil) by the use of some machine learning algorithms. As a conclusion, the results highlight the potential of RDA factors in prediction and classification because they appreciably improve the results obtained from PCA factors in calibration and validation.

The NtrYX Two-Component System of Paracoccus denitrificans Is Required for the Maintenance of Cellular Iron Homeostasis and for a Complete Denitrification under Iron-Limited Conditions.

Denitrification consists of the sequential reduction of nitrate to nitrite, nitric oxide, nitrous oxide, and dinitrogen. Nitrous oxide escapes to the atmosphere, depending on copper availability and other environmental factors. Iron is also a key element because many proteins involved in denitrification contain iron-sulfur or heme centers. The NtrYX two-component regulatory system mediates the responses in a variety of metabolic processes, including denitrification. A quantitative proteomic analysis of a Paracoccus denitrificans NtrY mutant grown under denitrifying conditions revealed the induction of different TonB-dependent siderophore transporters and proteins related to iron homeostasis. This mutant showed lower intracellular iron content than the wild-type strain, and a reduced growth under denitrifying conditions in iron-limited media. Under iron-rich conditions, it releases higher concentrations of siderophores and displayes lower nitrous oxide reductase (NosZ) activity than the wild-type, thus leading to nitrous oxide emission. Bioinformatic and qRT-PCR analyses revealed that NtrYX is a global transcriptional regulatory system that responds to iron starvation and, in turn, controls expression of the iron-responsive regulators fur, rirA, and iscR, the denitrification regulators fnrP and narR, the nitric oxide-responsive regulator nnrS, and a wide set of genes, including the cd1-nitrite reductase NirS, nitrate/nitrite transporters and energy electron transport proteins.

Contextual memory reactivation modulates Ca2+-activity network state in a mushroom body-like center of the crab N. granulata.

High-order brain centers play key roles in sensory integration and cognition. In arthropods, much is known about the insect high-order centers that support associative memory processes, the mushroom bodies. The hypothesis that crustaceans possess structures equivalent to the mushroom bodies -traditionally called hemiellipsoid body- has been receiving neuroanatomical endorsement. The recent functional support is limited to the short term: in a structure of the true crab Neohelice granulata that has many insect-like mushroom bodies traits, the plastic learning changes express the context attribute of an associative memory trace. Here, we used in vivo calcium imaging to test whether neuronal activity in this structure is associated with memory reactivation in the long-term (i.e., 24 h after training). Long-term training effects were tested by presenting the training-context alone, a reminder known to trigger memory reconsolidation. We found similar spontaneous activity between trained and naïve animals. However, after training-context presentation, trained animals showed increased calcium events rate, suggesting that memory reactivation induced a change in the underlying physiological state of this center. Reflecting the change in the escape response observed in the paradigm, animals trained with a visual danger stimulus showed significantly lower calcium-evoked transients in the insect-like mushroom body. Protein synthesis inhibitor cycloheximide administered during consolidation prevented calcium mediated changes. Moreover, we found the presence of distinct calcium activity spatial patterns. Results suggest that intrinsic neurons of this crustacean mushroom body-like center are involved in contextual associative long-term memory processes.

A familiar study on self-limited childhood epilepsy patients using hIPSC-derived neurons shows a bias towards immaturity at the morphological, electrophysiological and gene expression levels.

BACKGROUND: Self-limited Childhood Epilepsies are the most prevalent epileptic syndrome in children. Its pathogenesis is unknown. In this disease, symptoms resolve spontaneously in approximately 50% of patients when maturity is reached, prompting to a maturation problem. The purpose of this study was to understand the molecular bases of this disease by generating and analyzing induced pluripotent stem cell-derived neurons from a family with 7 siblings, among whom 4 suffer from this disease. METHODS: Two affected siblings and, as controls, a healthy sister and the unaffected mother of the family were studied. Using exome sequencing, a homozygous variant in the FYVE, RhoGEF and PH Domain Containing 6 gene was identified in the patients as a putative genetic factor that could contribute to the development of this familial disorder. After informed consent was signed, skin biopsies from the 4 individuals were collected, fibroblasts were derived and reprogrammed and neurons were generated and characterized by markers and electrophysiology. Morphological, electrophysiological and gene expression analyses were performed on these neurons. RESULTS: Bona fide induced pluripotent stem cells and derived neurons could be generated in all cases. Overall, there were no major shifts in neuronal marker expression among patient and control-derived neurons. Compared to two familial controls, neurons from patients showed shorter axonal length, a dramatic reduction in synapsin-1 levels and cytoskeleton disorganization. In addition, neurons from patients developed a lower action potential threshold with time of in vitro differentiation and the amount of current needed to elicit an action potential (rheobase) was smaller in cells recorded from NE derived from patients at 12 weeks of differentiation when compared with shorter times in culture. These results indicate an increased excitability in patient cells that emerges with the time in culture. Finally, functional genomic analysis showed a biased towards immaturity in patient-derived neurons. CONCLUSIONS: We are reporting the first in vitro model of self-limited childhood epilepsy, providing the cellular bases for future in-depth studies to understand its pathogenesis. Our results show patient-specific neuronal features reflecting immaturity, in resonance with the course of the disease and previous imaging studies.

Effect of pH on the denitrification proteome of the soil bacterium Paracoccus denitrificans PD1222.

Denitrification is a respiratory process by which nitrate is reduced to dinitrogen. Incomplete denitrification results in the emission of the greenhouse gas nitrous oxide and this is potentiated in acidic soils, which display reduced denitrification rates and high N2O/N2 ratios compared to alkaline soils. In this work, impact of pH on the proteome of the soil denitrifying bacterium Paracoccus denitrificans PD1222 was analysed with nitrate as sole energy and nitrogen source under anaerobic conditions at pH ranging from 6.5 to 7.5. Quantitative proteomic analysis revealed that the highest difference in protein representation was observed when the proteome at pH 6.5 was compared to the reference proteome at pH 7.2. However, this difference in the extracellular pH was not enough to produce modification of intracellular pH, which was maintained at 6.5 ± 0.1. The biosynthetic pathways of several cofactors relevant for denitrification and nitrogen assimilation like cobalamin, riboflavin, molybdopterin and nicotinamide were negatively affected at pH 6.5. In addition, peptide representation of reductases involved in nitrate assimilation and denitrification were reduced at pH 6.5. Data highlight the strong negative impact of pH on NosZ synthesis and intracellular copper content, thus impairing active NosZ assembly and, in turn, leading to elevated nitrous oxide emissions.

Maternal smoking during pregnancy and physiological anxiety in children with attention deficit hyperactivity disorder.

Our objective was to explore the relationship between mother smoking during pregnancy and physiological anxiety of children with Attention deficit-hyperactivity disorder. Cognitive profile was evaluated by Wechsler Intelligence Scale for Children, physiological anxiety by Children's Manifest Anxiety Scale. Mother's smoking was evaluated by the Fagerström test for nicotine dependence. Ninety-seven children with Attention Deficit-Hyperactivity Disorder combined type, 70 inattentive, and 48 hyperactive-impulsive, and 130 controls were studied. We found a higher frequency of high smoking dependence in mothers of children with Attention Deficit-Hyperactivity Disorder-combined type, and Attention Deficit Hyperactivity Disorder-hyperactive type in the Fagerström test; and a significant correlation between physiological anxiety in children with Attention Deficit Hyperactivity Disorder-combined type, with high and moderate maternal smoking level during pregnancy. In conclusion, data suggests, with caution a brain alteration of infants, induced by nicotine exposure during pregnancy in children with Attention Deficit Hyperactivity Disorder-combined type, and Attention Deficit Hyperactivity Disorder-hyperactive type.

Simultaneous administration of cocaine and caffeine dysregulates HCN and T-type channels.

RATIONALE: The abuse of psychostimulants has adverse consequences on the physiology of the central nervous system. In Argentina, and other South American countries, coca paste or "PACO" (cocaine and caffeine are its major components) is massively consumed with deleterious clinical consequences for the health and well-being of the general population. A scant number of studies have addressed the consequences of stimulant combination of cocaine and caffeine on the physiology of the somatosensory thalamocortical (ThCo) system. OBJECTIVES: Our aim was to study ion conductances that have important implications regulating sleep-wake states 24-h after an acute or chronic binge-like administration of a cocaine and caffeine mixture following previously analyzed pasta base samples ("PACO"-like binge") using mice. METHODS: We randomly injected (i.p.) male C57BL/6JFcen mice with a binge-like psychostimulants regimen during either 1 day (acute) or 1 day on/1 day off during 13 days for a total of 7 binges (chronic). Single-cell patch-clamp recordings of VB neurons were performed in thalamocortical slices 24 h after the last psychostimulant injection. We also recorded EEG/EMG from mice 24 h after being systemically treated with chronic administration of cocaine + caffeine versus saline, vehicle. RESULTS: Our results showed notorious changes in the intrinsic properties of the VB nucleus neurons that persist after 24-h of either acute or chronic binge administrations of combined cocaine and caffeine ("PACO"-like binge). Functional dysregulation of HCN (hyperpolarization-activated cyclic nucleotide-gated) and T-type VGC (voltage-gated calcium) channels was described 24-h after acute/chronic "PACO"-like administrations. Furthermore, intracellular basal [Ca2+] disturbances resulted a key factor that modulated the availability and the activation of T-type channels, altering T-type "window currents." As a result, all these changes ultimately shaped the low-threshold spikes (LTS)-associated Ca2+ transients, regulated the membrane excitability, and altered sleep-wake transitions. CONCLUSION: Our results suggest that deleterious consequences of stimulants cocaine and caffeine combination on the thalamocortical physiology as a whole might be related to potential neurotoxic effects of soaring intracellular [Ca2+].

Hydrogen Production through Glycerol Photoreforming on TiO2/Mesoporous Carbon: Influence of the Synthetic Method.

This article explores the effect of the synthetic method of titanium dioxide (TiO2)/C composites (physical mixture and the water-assisted/unassisted sol-gel method) on their photocatalytic activity for hydrogen production through glycerol photoreforming. The article demonstrates that, apart from a high surface area of carbon and the previous activation of its surface to favor titania incorporation, the appropriate control of titania formation is crucial. In this sense, even though the amount of incorporated titania was limited by the saturation of carbon surface groups (in our case, ca. 10 wt.% TiO2), the sol-gel process without water addition seemed to be the best method, ensuring the formation of small homogeneously-distributed anatase crystals on mesoporous carbon. In this way, a ca. 110-fold increase in catalyst activity compared to Evonik P25 (expressed as hydrogen micromole per grams of titania) was achieved.

Olive Leaves as Biotemplates for Enhanced Solar-Light Harvesting by a Titania-Based Solid.

Olive leaves (by-product from olive oil production in olive mills) were used as biotemplates to synthesize a titania-based artificial olive leaf (AOL). Scanning electron microscopy (SEM) images of AOL showed the successful replication of trichomes and internal structure channels present in olive leaves. The BET surface area of AOL was 52 m2·g-1. X-ray diffraction (XRD) and Raman spectra revealed that the resulting solid was in the predominantly-anatase crystalline form (7.5 nm average particle size). Moreover, the synthesis led to a red-shift in light absorption as compared to reference anatase (gap energies of 2.98 and 3.2 eV, respectively). The presence of surface defects (as evidenced by X-ray photoelectron spectroscopy, XPS, and electron paramagnetic resonance spectroscopy, EPR) and doping elements (e.g., 1% nitrogen, observed by elemental analysis and XPS) could account for that. AOL was preliminarily tested as a catalyst for hydrogen production through glycerol photoreforming and exhibited an activity 64% higher than reference material Evonik P25 under solar irradiation and 144% greater under ultraviolet radiation, (under voltage) UV.

Acute Regulation of the Arousal-Enhancing Drugs Caffeine and Modafinil on Class IIa HDACs In Vivo and In Vitro: Focus on HDAC7.

Psychostimulant drugs, such as modafinil and caffeine, induce transcriptional alterations through the dysregulation of epigenetic mechanisms. We have previously demonstrated that acute modafinil administration is accompanied by multiple changes in the expression of histone deacetylases (HDACs) within the mouse medial prefrontal cortex (mPFC). Herein, we compared alterations in class IIa HDACs in the mouse mPFC and dorsal striatum (DS) after a single exposure to each psychostimulant. We treated male C57BL/6 mice with modafinil (90 mg/kg, i.p.), caffeine (10 mg/kg, i.p.), or vehicle and evaluated locomotor activity. Following, we examined hdac4, hdac5, and hdac7 mRNA expression using qRT-PCR and HDAC7, pHDAC7, and pHDACs4/5/7 using Western blot. Last, we explored generalized effects in N2a cell line using modafinil (100 µM and 1 mM) or caffeine (80 µM and 800 µM). Our results indicate that modafinil had greater effects on locomotor activity compared with caffeine. qRT-PCR experiments revealed that modafinil decreased hdac5 and hdac7 mRNA expression in the DS, while caffeine had no effects. In the mPFC, modafinil increased hdac7 mRNA expression, with no effects observed for caffeine. Western blot revealed that within the DS, modafinil induced increases in HDAC7, pHDAC7, and pHDACs4/5/7 protein expression, while, in the mPFC, caffeine induced decreases in HDAC7, pHDAC7, and pHDACs4/5/7 protein levels. In vitro studies revealed that modafinil increased hdac4, hdac5, and hdac7 mRNA levels in N2a, while caffeine only increased hdac5 at a higher dose. These findings support the notion that modafinil and caffeine exert distinct regulation of class IIa HDAC family members and that these transcriptional and translational consequences are region-specific.

Functional approach and agro-climatic information to improve the estimation of olive oil fatty acid content from near-infrared data.

Extra virgin olive oil (EVOO) is very appreciated by its taste, flavor, and benefits for health, and so, it has a high price of commercialization. This fact makes it necessary to provide reliable and cost-effective analytical procedures, such as near-infrared (NIR) spectroscopy, to analyze its traceability and purity, in combination with chemometrics. Fatty acids profile of EVOO, considered as a quality parameter, is estimated, firstly, from NIR data and, secondly, by adding agro-climatic information. NIR and agro-climatic data sets are summarized by using principal component analysis (PCA) and treated by both scalar and functional approaches. The corresponding PCA and FPCA are progressively introduced in regression models, whose goodness of fit is evaluated by the dimensionless root-mean-square error. In general, SFAs, MUFAs, and PUFAs (and disaggregated fatty acids) estimations are improved by adding agro-climatic besides NIR information (mainly, temperature or evapotranspiration) and considering a functional point of view for both NIR and agro-climatic data.

Differential effects of HDAC inhibitors on PPN oscillatory activity in vivo.

The pedunculopontine nucleus (PPN) has long been known to be part of the reticular activating system (RAS) in charge of arousal and REM sleep. We previously showed that in vitro exposure to a HDAC Class I and II mixed inhibitor (TSA), or a specific HDAC class IIa inhibitor (MC 1568), decreased PPN gamma oscillations. Given the lack of information on systemic in vivo treatments on neuronal synaptic properties, the present study was designed to investigate the systemic effect of HDAC inhibitors (HDACi) on PPN rhythmicity. Rat pups were injected (acute, single dose) with TSA (4 or 20 mg/kg), MC1568 (4 or 20 mg/kg), or MS275 (20 or 100 mg/kg). Our results show that MC1568 (20 mg/kg) reduced mean frequency of PPN oscillations at gamma band, while increasing mean input resistance (Rm) of PPN neurons. For TSA (4 and 20 mg/kg), we observed reduced mean frequency of oscillations at gamma band and increased mean Rm of PPN neurons. Systemic administration of 20 mg/kg MC1568 and TSA effects on Rm were washed out after 60 min of in vitro incubation of PPN slices, suggesting an underlying functional recovery of PPN calcium-mediated gamma band oscillations over time. In addition, at a lower dose, 4 mg/kg, MC1568 and TSA induced higher mean amplitude gamma oscillations. Blocking HDAC class I might not have deleterious effects on gamma activity, but, more importantly, the inhibition of HDAC class I (at 100 mg/kg) increased gamma band oscillations. In conclusion, the present results in vivo validate our previous findings in vitro and further expand information on the effects of HDAC inhibition on PPN rhythmicity. PPN neurons require normal activity of HDAC class IIa in order to oscillate at gamma band.

Gamma oscillations in the pedunculopontine nucleus are regulated by F-actin: neuroepigenetic implications.

The pedunculopontine nucleus (PPN) is part of the reticular activating system (RAS) in charge of arousal and rapid eye movement sleep. The presence of high-frequency membrane oscillations in the gamma-band range in the PPN has been extensively demonstrated both in vivo and in vitro. Our group previously described histone deacetylation (HDAC) inhibition in vitro induced protein changes in F-actin cytoskeleton and intracellular Ca2+ concentration regulation proteins in the PPN. Here, we present evidence that supports the presence of a fine balance between HDAC function and calcium calmodulin kinase II-F-actin interactions in the PPN. We modified F-actin polymerization in vitro by using jasplakinolide (1 µM, a promoter of F-actin stabilization), or latrunculin-B (1 µM, an inhibitor of actin polymerization). Our results showed that shifting the balance in either direction significantly reduced PPN gamma oscillation as well as voltage-dependent calcium currents.

HDAC superfamily promoters acetylation is differentially regulated by modafinil and methamphetamine in the mouse medial prefrontal cortex.

Dysregulation of histone deacetylases (HDAC) has been proposed as a potential contributor to aberrant transcriptional profiles that can lead to changes in cognitive functions. It is known that METH negatively impacts the prefrontal cortex (PFC) leading to cognitive decline and addiction whereas modafinil enhances cognition and has a low abuse liability. We investigated if modafinil (90 mg/kg) and methamphetmine (METH) (1 mg/kg) may differentially influence the acetylation status of histones 3 and 4 (H3ac and H4ac) at proximal promoters of class I, II, III, and IV HDACs. We found that METH produced broader acetylation effects in comparison with modafinil in the medial PFC. For single dose, METH affected H4ac by increasing its acetylation at class I Hdac1 and class IIb Hdac10, decreasing it at class IIa Hdac4 and Hdac5. Modafinil increased H3ac and decreased H4ac of Hdac7. For mRNA, single-dose METH increased Hdac4 and modafinil increased Hdac7 expression. For repeated treatments (4 d after daily injections over 7 d), we found specific effects only for METH. We found that METH increased H4ac in class IIa Hdac4 and Hdac5 and decreased H3/H4ac at class I Hdac1, Hdac2, and Hdac8. At the mRNA level, repeated METH increased Hdac4 and decreased Hdac2. Class III and IV HDACs were only responsive to repeated treatments, where METH affected the H3/H4ac status of Sirt2, Sirt3, Sirt7, and Hdac11. Our results suggest that HDAC targets linked to the effects of modafinil and METH may be related to the cognitive-enhancing vs cognitive-impairing effects of these psychostimulants.