Cortex Of Rats Research Articles

Early metabolic changes in the brain of Alzheimer's disease rats are driven by GLAST+ cells.

Glucose metabolic dysfunction is a hallmark of Alzheimer's disease (AD) pathology and is used to diagnose the disease or predict imminent cognitive decline. The main method to measure brain metabolism in vivo is positron emission tomography with 2-Deoxy-2-[18F]fluoroglucose ([18F]FDG-PET). The cellular origin of changes in the [18F]FDG-PET signal in AD is controversial. We addressed this by combining [18F]FDG-PET with subsequent cell-sorting and γ-counting of [18F]FDG-accumulation in sorted cell populations. 7-month-old male TgF344-AD rats and wild-type controls (n = 24/group) received sham or ceftriaxone (200 mg/kg) injection prior to [18F]FDG-PET imaging to increase glutamate uptake and glucose utilisation. The same animals were injected again one week later, and radiolabelled brains were dissected, with hippocampi taken for magnetically-activated cell sorting of radioligand-treated tissues (MACS-RTT). Radioactivity in sorted cell populations was measured to quantify cell-specific [18F]FDG uptake. Transcriptional analyses of metabolic enzymes/transporters were also performed. Hypometabolism in the frontal association cortex of TgF344-AD rats was identified using [18F]FDG-PET, whereas hypermetabolism was identified in the hippocampus using MACS-RTT. Hypermetabolism was primarily driven by GLAST+ cells. This was supported by transcriptional analyses which showed alteration to metabolic apparatus, including upregulation of hexokinase 2 and altered expression of glucose/lactate transporters. See Figure 1 for summary.

Berberine Inhibits Migration and Apoptosis of Rat Podocytes in Diabetic Nephropathy via the Novel lncRNA LOC102549726 Related Pathway.

Diabetic nephropathy (DN) stands as one of the most severe complications of diabetes. Podocytes injury, particularly its attachment to the lateral glomerular basement membrane, serves as a crucial indicator of DN. Growing evidence suggests that berberine (BBR) can mitigate the onset and progression of DN. However, the molecular mechanisms through which BBR exerts its beneficial effects in the treatment of DN remain incompletely elucidated. To explore the underlying mechanisms by which BBR exerts its therapeutic effects in DN. High-throughput lncRNA sequencing on the renal cortex of both the DN model group and the normal SD group was performed to dig for differentially expressed lncRNAs. The expression of LOC102549726 was evaluated using qPCR. The biological functions of LOC102549726 were analyzed in podocyets and DN rats. The bioinformatics techniques, qPCR and WB were used to explore the potential molecular mechanisms. We found that lncRNA LOC102549726 was highly expressed in renal cortex of DN rats and podocytes subjected to high glucose conditions. Silencing LOC102549726 inhibited migration and apoptosis of podocytes. Mechanistically, LOC102549726 was identified as a facilitator of the expression of EGF and forkhead box O1 (FOXO1). BBR, a known therapeutic agent for DN, exhibited the ability to diminish the level of LOC102549726, EGF and FOXO1 in both DN rats and podocytes. Our findings suggested that BBR suppresses migration and apoptosis of podocytes in DN through targeting the LOC102549726/EGF/FOXO1 axis. This sheds light on a potential therapeutic avenue for mitigating the impact of DN on podocyte function.

Low dose deltamethrin exposure affects gene expression in rat frontal cortex

Pyrethroids are a class of commonly used synthetic insecticides, widely used in agricultural and residential settings due to their efficacy and relatively low environmental impact. Nonetheless, epidemiological studies have found that exposure to pyrethroids during developmental stages is linked to risk for neurodevelopmental disorders. However, the molecular mechanisms behind these neurotoxic effects remain unclear. Our study investigates the impact of oral exposure to deltamethrin, a widely used Type II pyrethroid pesticide, on gene expression in the frontal cortex of rats. We used differential gene expression data from frontal cortex dissections from male Long-Evans rats exposed to a 3 mg/kg oral dose of deltamethrin (or vehicle) to perform a 3Pod analysis in R Studio, which included GSEA, Enrichr, and iLINCS analyses. We found that rats who were exposed to deltamethrin had significant changes in gene expression in cortex in pathways related to inflammation, apoptosis, cellular energy metabolism, and synapses. Our study provides important insight on the effects of pesticide exposure on the brain and possible treatments and preventions. This study also emphasizes the need for further research on pyrethroid pesticides and their relationship to neurodevelopmental disorders.

Abstract TP345: Electronic Cigarette Exposure Worsens Stroke Induced Inflammation in Female Rats

Introduction: The rise in popularity of nicotine-containing electronic cigarettes (ECs) globally necessitates a deeper understanding of their effects on stroke outcomes. This study investigates the influence of EC exposure on post-ischemic inflammation. Methods: Adult Sprague-Dawley rats of both sexes were randomly assigned to either air or EC vapor exposure (5% nicotine Juul pods) for 16 nights, followed by transient middle cerebral artery occlusion (tMCAO; 90 minutes) or sham surgery. Post-surgery, animals were divided into two cohorts. In the first cohort, cortical brain tissue was collected 24 hours after tMCAO or sham surgery for Western blot analysis of inflammasome proteins, including Caspase-1, Interleukin-1β (IL-1β), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and gasdermin-D (GSDMD). The second cohort was sacrificed 21 days post-tMCAO for immunohistochemical analysis of microglial marker ionized calcium-binding adapter molecule-1 (Iba-1). De-ramified microglia were quantified across three serial coronal sections (10 μm) using the optical fractionator probe in StereoInvestigator software, with a counting frame of 100x100 μm and approximately 40 sampling sites per section. Microglial morphology and Sholl analysis were performed by capturing three cortical images per slide, each containing at least three microglia, and across three slides per subject, resulting in 18 images for peri-infarct and contralateral areas. Analysis was conducted using ImageJ software. Results: Western blot analysis revealed a significant increase in Caspase-1 and ASC protein levels in the ipsilateral cortex of EC-exposed female rats compared to males after tMCAO (p<0.05). Quantification of Iba-1 indicated an increase in de-ramified microglia in the cortex of EC-exposed female rats as compared to air-exposed after tMCAO, potentially exacerbating post-stroke infarction. Microglial morphology analysis showed increased cell soma size and decreased branch length in EC-exposed female rats. Sholl analysis demonstrated reduced microglial complexity in EC-exposed group as compared to air-exposed after tMCAO, with a smaller area under the curve and fewer peak intersections in the cortex. Conclusion: EC exposure exacerbates stroke-induced inflammation and cognitive deficits in female rats. Future research should explore whether EC withdrawal mitigates ischemic severity and determine the necessary duration of withdrawal for potential recovery.

Abstract TP375: Ischemic Insult Under Hyperhomocysteinemic Condition Triggers Early Onset Of Inflammatory Response Causing Exacerbation Of Brain Injury

Hyperhomocysteinemia, a metabolic disorder characterized by systemic elevation of amino acid homocysteine, is linked to deficiency in vitamins and enzymes involved in homocysteine metabolism. The incidence of hyperhomocysteinemia is high in the elderly population due to reduced micronutrient absorption and metabolism. Recent preclinical studies in animal models of stroke showed that predisposition to hyperhomocysteinemia exacerbates ischemic brain injury and worsens behavioral deficits, establishing hyperhomocysteinemia as a potential comorbidity for stroke. These studies further showed that hyperhomocysteinemia-induced stimulation of GluN2A subunit containing NMDA receptors (GluN2A-NMDARs) in conjunction with glutamate-induced stimulation of GluN2B subunit containing NMDARs (GluN2B-NMDARs) exacerbates stroke pathology. However, the precise intracellular mechanisms involved in such exacerbation of ischemic brain injury is not known. The current study sought to investigate whether under hyperhomocysteinemic condition GluN2A-NMDAR mediated early activation of the transcription factor Nuclear Factor-κB (NFκB) and subsequent expression of the pro-inflammatory chemokine Monocyte chemoattractant protein-1 (MCP-1) enhances post-ischemic inflammatory response and exacerbation of brain damage. Adult male Wistar rats were made hyperhomocysteinemic by implantation of Alzet osmotic pumps containing L-homocysteine. The animals were hyperhomocysteinemic within 3 days with a total plasma homocysteine level of ~24 μM. Acute ischemic stroke was induced by middle cerebral artery occlusion for 60 min followed by reperfusion (6h). Brain tissues were processed for MCP-1 ELISA and RT-PCR. A significant increase in MCP-1 mRNA and protein levels were observed in the ipsilateral cortex of hyperhomocysteinemic rats compared to control rats within 6h of reperfusion. An accelerated brain damage was also observed at this time in the hyperhomocysteinemic rats. Inhibition of GluN2A-NMDAR (NVP-AAM077, i.v.) and NFκB (BMS345541, IKK inhibitor; i.p) at the onset of ischemic insult attenuated increase in MCP-1 mRNA and protein levels, as well as exacerbation of brain injury under hyperhomocysteinemic condition. The study provides compelling evidence for a novel role of GluN2A-NMDAR in promoting neuro-inflammatory response that contributes to exacerbation of stroke pathology under hyperhomocysteinemic condition.

Cholinergic neurotransmission in the brain of streptozotocin-induced rat model of sporadic Alzheimer's disease: long-term follow up.

Rats treated intracerebroventricularly with streptozotocin (STZ-icv) develop pathologic features, which resemble those in Alzheimer's disease and have been proposed as a non-transgenic model for sporadic type of the disease (sAD). We aimed to characterize cholinergic transmission in the rat brain as a function of STZ-icv dose and time after the treatment. Acetylcholinesterase (AChE) activity and expression of muscarinic (M1, M4) and nicotinic (α7) receptors, cholin acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) were measured in hippocampus (HPC) and parietotemporal cortex (CTX) of STZ-icv and age-matched control rats one week, and one, three, six and nine months after the icv administration of STZ (0.3, 1 and 3mg/kg), respectively. Cholinergic and astroglial changes were found most pronounced with a highest STZ dose in time-dependent manner. The cortex and hippocampus exhibited specific alterations in cholinergic transmission following STZ-icv administration, with either similar or distinct patterns depending on the parameter observed: increased AChE activity in HPC and invariable in CTX; increased M4 and ChAT levels in both regions; substantial cortical M1 level increment and moderate hippocampal M1 decrement; and decreased α7 levels in both regions, with subsequent increase observed only in HPC. Alterations in cerebral cholinergic neurotransmission in STZ-icv rat model were mostly following a threephasic time pattern: acute response (Phase I), complete/partial compensation (Phase II), and reappearance/progression of changes (Phase III). Staging structure of cholinergic changes in STZ-icv rat model might be speculated to partly correlate with cholinergic pathology in clinical AD stages.

The Secretome of Brain Endothelial Cells Exposed to the Pyrrolizidine Alkaloid Monocrotaline Induces Astrocyte Reactivity and Is Neurotoxic

Monocrotaline (MCT) has well-characterized hepatotoxic and pneumotoxic effects attributed to its active pyrrole metabolites. Studies have previously shown that astrocytes and neurons are targets of MCT, and that toxicity is attributed to astrocyte P450 metabolism to reactive metabolites. However, little is known about MCT toxicity and metabolism by brain endothelial cells (BECs), cells that, together with astrocytes, are specialized in xenobiotic metabolism and neuroprotection. Therefore, in the present study, we evaluated the toxicity of MCT in BECs, and the effects on astrocyte reactivity and neuronal viability in vitro. MCT was purified from Crotalaria retusa seeds. BECs, obtained from the brain of adult Wistar rats, were treated with MCT (1–500 µM), and cell viability and morphology were analyzed after 24–72 h of treatment. Astrocyte/neuron co-cultures were prepared from the cortex of neonatal and embryonic Wistar rats, and the cultures were exposed to conditioned medium (secretome) derived from BECs previously treated with MCT (100–500 µM, SBECM100/500). MCT was not toxic to BECs at the concentrations used and induced a concentration-dependent increase in cell dehydrogenase after 72 h of treatment, suggesting resistance to damage and drug metabolism. However, exposure of astrocyte/neuron co-cultures to the SBECM for 24 h induced changes in the cell morphology, vacuolization, and overexpression of GFAP in astrocytes, characterizing astrogliosis, and neurotoxicity with a reduction in the length of neurites labeled for β-III-tubulin, effects that were MCT concentration-dependent. These results support the hypothesis that MCT neurotoxicity may be due to products of its metabolism by components of the BBB such as BECs and astrocytes, which may be responsible for the brain lesions and symptoms observed after intoxication.

Potential effects of induced focal ischemia in the motor cortex of rats undergoing experimental periodontitis

Potential effects of induced focal ischemia in the motor cortex of rats undergoing experimental periodontitis

The protective efficacy of omega-3 polyunsaturated fatty acids on oxidative stress, inflammation, neurotransmitter perturbations, and apoptosis induced by monosodium glutamate in the brain of male rats

Exaggerated neuronal excitation by glutamate is a well-known cause of excitotoxicity, a key factor in numerous neurodegenerative disorders. This study examined the neurotoxic effect of monosodium glutamate (MSG) in the brain cortex of rats and focused on assessing the potential neuroprotective effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs). Four groups of adult male rats (n = 10) were assigned as follows; normal control, ω-3 PUFAs (400 mg/kg) alone, MSG (4 mg/g) alone, and MSG plus ω-3 PUFAs (4 mg/g MSG plus 400 mg/kg ω-3 PUFAs). Biochemical analysis, immunohistochemical, and histological examinations were conducted upon completion of the treatment protocol. Results revealed that MSG significantly increased malondialdehyde, nitric oxide, tumor necrosis factor-α, interleukin 1β, acetylcholinesterase, monoamine oxidase, and caspase-3. However, the MSG-treated group showed a decline in reduced glutathione, catalase, superoxide dismutase, dopamine, and serotonin. In addition, MSG caused histopathological changes in the cortical region which support the biochemical and immunohistochemical analysis. Supplementation of ω-3 PUFAs greatly improved the biochemical, immunohistochemical, and histopathological alterations induced by MSG administration in the brain cortex. Together, these findings revealed a neuroprotective effect of ω-3 PUFAs against MSG-induced toxicity in the brain cortex by attenuating oxidative damage, inflammation, neurochemical perturbations, and apoptosis.Graphical abstract

Melatonin influence on miRNA expression in sperm, hypothalamus, pre-frontal cortex and cerebellum of Wistar rats.

Melatonin is a pineal hormone synthesized exclusively at night, in several organisms. Its action on sperm is of particular interest, since they transfer genetic and epigenetic information to the offspring, including microRNAs, configuring a mechanism of paternal epigenetic inheritance. MicroRNAs are known to participate in a wide variety of mechanisms in basically all cells and tissues, including the brain and the sperm cells, which are known, respectively, to present 70% of all identified microRNAs and to transfer these molecules to the embryo. MicroRNAs from sperm have been associated with modulation of embryonic development and inheritance of psychiatric symptoms, including autism. Given that microRNAs and melatonin are ubiquitous molecules with important roles in the organism, the aim of this study was to investigate the expression of specific microRNAs in sperm, brain and cerebellum of pinealectomized rats. For this study, Wistar rats had their pineal gland removed at 60 post-partum. Part of these rats received exogenous melatonin until the day of the euthanasia. The control group did not receive any treatment or manipulation. The sperm, hypothalamus, prefrontal cortex and cerebellum were collected for analysis of microRNA expression by RT-qPCR. The results suggest that melatonin absence caused by pinealectomy increases the expression of the target microRNAs in the sperm. Although the data suggest an alteration (increase or decrease depending on the region and microRNA) of expression levels of some microRNAs in the brain and cerebellum of pinealectomized rats, the differences were not statistically significant. This seems to be a consequence of the intragroup variation. Melatonin administration restored the levels of the target microRNAs in the sperm. Additional studies are needed to understand the impact of the alterations of microRNA expression to the pinealectomized rats as well as to their descendants.

The Effect of Disulfiram and N-Acetylcysteine, Potential Compensators for Sulfur Disorders, on Lipopolysaccharide-Induced Neuroinflammation Leading to Memory Impairment and the Metabolism of L-Cysteine Disturbance

Background: The role of sulfur-containing drugs, disulfiram (DSF) and N-acetylcysteine (NAC), in alleviating neuroinflammation is poorly understood. The objective of this study was to examine the effect of DSF and NAC on memory and on the metabolism of L-cysteine and inflammation-related parameters in the cerebral cortex of rats in a model of neuroinflammation induced by the administration of lipopolysaccharide (LPS). Methods: All the treatments were administered intraperitoneally for 10 days (LPS at a dose of 0.5 mg/kg b.w., DSF at a dose of 100 mg/kg b.w, and NAC at a dose of 100 mg/kg b.w.). Behavior was evaluated by the novel object recognition (NOR) test and object location (OL) test, and the level of brain-derived neurotrophic factor (BDNF) was assayed to evaluate neuronal functioning. Cerebral cortex homogenates were tested for hydrogen sulfide (H2S), sulfane sulfur, sulfates, non-protein sulfhydryl groups (NPSH), nitric oxide (NO), and reactive oxygen species (ROS) by biochemical analysis. Results: Neither DSF nor NAC alleviated LPS-induced memory disorders estimated by the NOR test and OL test. The studied compounds also did not affect significantly the levels of BDNF, ROS, NO, H2S, and sulfane sulfur in the cerebral cortex. However, we observed an increase in sulfate concentration in brain tissues after LPS treatment, while DSF and NAC caused an additional increase in sulfate concentration. On the other hand, our study showed that the administration of DSF or NAC together with LPS significantly enhanced the cortical level of NPSH, of which glutathione is the main component. Conclusions: Our study did not confirm the suggested potential of DSF and NAC to correct memory disorders; however, it corroborated the notion that they reduced oxidative stress induced by LPS by increasing the NPSH level. Additionally, our study showed an increase in sulfate concentration in the brain tissues after LPS treatment, which means the upregulation of sulfite and sulfate production in inflammatory conditions.

Synaptic phosphoproteome modifications and cortical circuit dysfunction are linked to the early-stage progression of alpha-synuclein aggregation.

Cortical dysfunction is increasingly recognized as a major contributor to the non-motor symptoms associated with Parkinson's disease (PD) and other synucleinopathies. Although functional alterations in cortical circuits have been observed in preclinical PD models, the underlying molecular mechanisms are unclear. To bridge this knowledge gap, we investigated tissue-level changes in the cortices of rats and mice treated with alpha-synuclein (aSyn) seeds using a multi-omics approach. Our study revealed significant phosphoproteomic changes, but not global proteomic or lipid profiling changes, in the rat sensorimotor cortex 3 months after intra-striatal injection with aSyn preformed fibrils (PFFs). Gene ontology analysis of the phosphoproteomic data indicated that PFF administration impacted pathways related to synaptic transmission and cytoskeletal organization. Similar phosphoproteomic perturbations were observed in the sensorimotor cortex of mice injected intrastriatally or intracortically with aSyn PFFs. Functional analyses demonstrated increased neuronal firing rates and enhanced spike-spike coherence in the sensorimotor cortices of PFF-treated mice, indicating seed-dependent cortical circuit dysfunction. Bioinformatic analysis of the altered phosphosites suggested the involvement of several kinases, including casein kinase-2 (CK2), which has been previously implicated in PD pathology. Collectively, these findings highlight the importance of phosphorylation-mediated signaling pathways in the cortical response to aSyn pathology spread in PD and related synucleinopathies, setting the stage for developing new therapeutic strategies.

Long‐Term Neural Recording Performance of PEDOT/CNT/Dexamethasone‐Coated Electrode Array Implanted in Visual Cortex of Rats

Implantable neural electrode arrays can be inserted in the brain to provide single‐cell electrophysiology recording for neuroscience research and brain–machine interface applications. However, maintaining signal quality over time is complicated by inflammatory tissue responses and degradation of electrode materials. Organic electrode coatings offer a solution by enhancing recording and stimulation capabilities, including reduced impedance, increased charge injection capacity, and the ability to incorporate and release anti‐inflammatory drugs. Herein, acid‐functionalized multiwalled carbon nanotubes (CNTs) loaded with dexamethasone (Dex) are incorporated into poly(3,4‐ethylendioxythiophene) (PEDOT) as electrode coatings. The electrochemical stability and recording performance of the PEDOT/CNT/Dex coating over an extended period of ≈18 months are investigated. Cyclic voltammetry (CV) stimulation is used to release Dex in half of the recording sites during the first 11 days of implantation to reduce the acute inflammation. The PEDOT/CNT/Dex‐coated floating microelectrode arrays demonstrate stable in vivo electrode impedance and successful detection of visually evoked neural activity from the rat visual cortex even at chronic time points. Additionally, the CV‐stimulated sites exhibit higher single‐unit (SU) recording yield, amplitudes, and signal‐to‐noise ratio compared to unstimulated sites. These results highlight the potential of anti‐inflammatory treatments to improve the quality and longevity of chronic neural recordings.

Bisdemethoxycurcumin mitigates traumatic brain injury in rats by modulating autophagy and oxidative stress via heat shock protein 90 alpha family class A member 1-mediated nuclear translocation of transcription factor EB.

Bisdemethoxycurcumin (BDMC), the primary active compound found in turmeric, exhibits diverse pharmacological properties. The study aimed to investigate the mechanisms underlying the protective effects of BDMC in traumatic brain injury (TBI). A rat TBI model was established using the Feeney's freefall epidural impact method, followed by BDMC treatment. Rat cortical neuron cells were exposed to hydrogen peroxide (H2O2) to induce oxidative stress and then treated with BDMC. The cells were also pretreated with autophagy inhibitor 3-MA and heat shock protein 90 alpha family class A member 1 (HSP90AA1) inhibitor 17-AAG. Additionally, the experiments also involved treating H2O2-exposed cortical neurons with 17-AAG and silencing HSP90AA1 expression. Co-immunoprecipitation was utilized to verify interactions between HSP90AA1 and transcription factor EB (TFEB), TFEB and nuclear factor erythroid 2 related factor 2 (Nrf2), and the localization of these complexes in the cytoplasm and nucleus. BDMC treatment significantly reduced modified neurological severity scores, brain water content, inflammatory infiltration, oxidative stress, and apoptosis in the cerebral cortex of TBI rats. Additionally, BDMC treatment elevated the expression of Beclin 1 and light chain 3 (LC3) II/LC3 I ratio while decreasing p62 expression. It also promoted TFEB nuclear translocation and increased HSP90AA1 levels in both the cytoplasm and nucleus, along with elevated nuclear Nrf2 expressions in TBI models. In vitro experiments showed decreased malondialdehyde levels, elevated glutathione peroxidase and superoxide dismutase levels upon BDMC treatment, along with repressed cortical neurons apoptosis, elevated Beclin 1 and LC3 II/LC3 I expressions, decreased p62 expressions, reduced cytoplasmic TFEB expression, increased nuclear TFEB and Nrf2 expression, and elevated HSP90AA1 expression in the cytoplasm and nucleus. Mechanistically, BDMC mediated autophagy and oxidative stress by activating HSP90AA1/TFEB/Nrf2 axis. Finally, HSP90AA1 was shown to regulate Nrf2 expression by binding to TFEB in the cellular model. BDMC alleviated TBI in rats by regulating autophagy and oxidative stress through HSP90AA1-mediated nuclear translocation of TFEB.

Exploring the Different Impacts of Ketamine on Neurotrophic Factors and Inflammatory Parameters in a Cecal Ligation and Puncture-Induced Sepsis Model.

Given ketamine's conflicting impacts on the central nervous system, investigating its effects within an inflammatory context becomes crucial. This study aimed to assess the impact of varying ketamine doses on neurotrophin and inflammatory cytokine levels within the brains of rats submitted to the sepsis model. Wistar rats were submitted to the cecal ligation and puncture (CLP) model of sepsis. Intraperitoneal ketamine injections (5, 15, or 25mg/kg) or saline were administered daily for seven days, thirty days post-CLP. Rats were euthanized thirty minutes following the last injection for analysis of IL-1β, IL-6, IL-10, TNF-α, BDNF, NGF, NT-3, and GDNF levels in the frontal cortex, hippocampus, and striatum. CLP-induced elevated IL-1𝛽, IL-6, IL-10, and TNF-α levels in the frontal cortex and hippocampus of rats, with reduced BDNF levels across all structures examined. Furthermore, reduced NGF and GDNF levels were observed solely in the hippocampus. Ketamine at 5mg/kg normalized CLP-induced alterations and, in Sham animals, increased BDNF and NGF levels in the frontal cortex and/or hippocampus. At 15mg/kg, ketamine elevated BDNF and NGF levels in Sham animals, while at 25mg/kg, it exacerbated the inflammatory response initiated by CLP. These findings suggest variable effects of ketamine within a context of systemic inflammation, emphasizing the importance of considering individual inflammatory backgrounds when utilizing ketamine.

PET Imaging of a Transgenic Tau Rat Model SHR24 with [18F]AV1451.

Positron Emission Tomography (PET) scans with radioligands targeting tau neurofibrillary tangles (NFT) have accelerated our understanding of the role of misfolded tau in neurodegeneration. While intended for human research, applying these radioligands to small animals establishes a vital translational link. Transgenic animal models of dementia, such as the tau rat SHR24, play a crucial role in enhancing our understanding of these disorders. This study aims to evaluate the utility of SHR24 rat model for PET studies. Dynamic PET scans were conducted in male SHR24 rats and their wild-type SHR (SHRwt) littermates using [18F]AV1451. Rapid blood sampling and metabolite analysis were performed to acquire input curves. Time activity curves were obtained from various brain regions over 60min. Blood-based, 2-Tissue Compartment Model (2-TCM) and Logan graphical analysis were used to obtain kinetic modelling parameters. The ability of reference tissue models to predict the binding potential (BPND) were assessed. Autoradiography studies were performed to corroborate the scan data. Total distribution volume (VT) was the best predicted parameter which revealed significantly higher uptake of [18F]AV1451 in the cortex (5.8 ± 1.1 vs 4.6 ± 0.7, P < 0.05) of SHR24 rats compared to SHRwt rats. Binding potential obtained from 2-TCM was variable, however BPND from reference tissue models detected significantly higher binding in cortex (0.28 ± 0.07 vs 0.20 ± 0.04, P < 0.01 by SRTM) and brainstem (0.14 ± 0.04 vs 0.08 ± 0.02, P < 0.01, by SRTM). With the ability to detect binding of established radioligand [18F]AV1451 in these rats, we have demonstrated the utility of this model for assessing aggregated tau neurobiology by PET, with reference tissue models providing potential for longitudinal studies.

L-carnitine protects against oxidative damage and neuroinflammation in cerebral cortex of rats submitted to chronic chemically-induced model of hyperphenylalaninemia.

Phenylketonuria is a genetic disorder characterized by high phenylalanine levels, the main toxic metabolite of the disease. Hyperphenylalaninemia can cause neurological impairment. In order to avoid this symptomatology, patients typically follow a phenylalanine-free diet supplemented with a synthetic formula that provides essential amino acids, including L-carnitine. This work aims to evaluate the potential neuroprotective effects of L-carnitine treatment in the cerebral cortex of rats submitted to a chronic chemically-induced model of Hyperphenylalaninemia, evaluating brain oxidative damage and neuroinflammation. We confirm the effectiveness of the animal model, through the increase of phenylalanine and L-carnitine in blood and cerebral cortex. L-carnitine treatment was effective in significantly decreasing the generation of reactive species and attenuating the superoxide dismutase (SOD) activity. Significant negative correlations between L-carnitine and superoxide dismutase as well as L-carnitine and reactive species generation were also found, reinforcing the involvement of oxidative stress and the effect of L-carnitine. Besides, L-carnitine attenuated the decrease in IL-4 levels, demonstrating both anti-inflammatory properties and a neuroprotective effect, through the decrease in the overexpression of the glial fibrillary acidic protein (GFAP) present in the cerebral cortex of rats with Hyperphenylalaninemia. Our results highlight the neuroprotective role of L-carnitine in the treatment of Phenylketonuria, mainly against neuroinflammation and the oxidative process, contributing to better clarify the pathophysiology of the disease.

Major individual and regional variations in unit entrainment by oscillations of different frequencies

In vitro studies have shown that a neuron’s electroresponsive properties can predispose it to oscillate at specific frequencies. In contrast, network activity in vivo can entrain neurons to rhythms that their biophysical properties do not predispose them to favor. However, there is limited information on the comparative frequency profile of unit entrainment across brain regions. Therefore, this study aimed to characterize the frequency profile of unit entrainment in cortex, thalamus, striatum, and basolateral amygdala (BLA) in rats of either sex. Neurons recorded simultaneously in a given brain region and behavioral state generally had very similar frequency profiles of unit entrainment. While cortical, striatal, and thalamic neurons were more strongly entrained by low than high local field potential (LFP) frequencies, increases in the power of these oscillations were linked to decreased firing rates for low frequencies versus increased firing rates for high frequencies. Deviating from this general trend, BLA neurons were more strongly entrained by high gamma than all other frequency bands in all subjects and states. By contrast, neurons in other regions displayed marked inter-individual variability. That is, although neurons in some regions had exceptionally high entrainment values in particular frequency bands, these were not observed consistently across rats. Based on these findings, some might infer that oscillations play a minor role or that different oscillatory patterns can support the same functions. Alternatively, the oscillations critical to brain function could be those not investigated here, namely those arising transiently in response to specific task variables or contexts. Perhaps those are less susceptible to genetic variations. While our findings do not allow us to determine which explanation is correct, they do highlight the perils of averaging.

Dietary Blueberry before and/or after Exposure to High Energy and Charge Particle Radiation Attenuates Neuroinflammation, Oxidative Stress, Glial Cell Activation, and Memory Deficits in Rats.

Acute neuroinflammatory and oxidative-stress (OS)-inducing stressors, such as high energy and charge (HZE) particle irradiation, produce accelerated aging in the brain. Anti-inflammatory and antioxidant foods, such as blueberries (BB), attenuate neuronal and cognitive deficits when administered to rodents before or both before and after HZE particle exposure. However, the effects of poststressor treatments are unknown and may be important to repair initial damage and prevent progressive neurodegeneration. This study assessed the differential efficacy and mechanistic targets of a BB-supplemented diet before and/or after HZE particle irradiation on neuroinflammation, OS, glial cell activation, and memory deficits. Two-mo-old male Sprague-Dawley rats (n = 120) consumed a 2% BB or control diet for 45 d. Rats were whole-body irradiated (150 cGy 56Fe) or were not irradiated, followed by a 45-d post-treatment interval in which they were fed a 2% BB or control diet. The novel object recognition (NOR) test was performed at the end of the post-treatment interval to evaluate memory. Biomarkers of neuroinflammation, OS, and glial cell activity were evaluated in the hippocampus and frontal cortex of rat brains after euthanasia. Statistical analyses included analysis of variance, t-tests, and Pearson correlations. Pre- and/or postirradiation BB treatments were similarly effective at reducing 56Fe-induced recognition memory deficits on the NOR and the protein and/or mRNA expression of neuroinflammatory factors (tumor necrosis factor-ɑ, inducible nitric oxide synthase, cyclooxygenase-2, phosphorylated IκB-α), 1 mediator of OS (NADPH oxidase), and markers for microglia and astrocyte activity (CD68 and glial fibrillary acidic protein) in the frontal cortex and hippocampus of rats 45 d postirradiation (P < 0.05). Findings support the use of dietary post-treatments with antioxidant and anti-inflammatory properties to attenuate biochemical changes in the brain and memory deficits after acute neuroinflammatory/OS-inducing stressors, in addition to having protective benefits.

Neural processing of auditory stimuli in rats: Translational aspects using auditory oddball paradigms.

The three-class oddball paradigm allows to investigate the processing of behaviorally relevant and irrelevant auditory stimuli. In humans, event-related potentials (ERPs) are used as neural correlate of behavior. We recorded local field potentials (LFPs) within the medial prefrontal cortex (mPFC) in rats during three-class and passive two-class oddball paradigms and analyzed the ERPs focusing on similarities to human recordings. Rats were trained in a three-class auditory oddball paradigm to respond by nose poke to an infrequent Target tone that was rewarded, while ignoring an infrequent Distractor and frequent Standard tone of different frequencies. After reaching a success criterion of correct responses to the Target and correct rejection of the Standard and Distractor (80 %,each), electrodes were stereotaxically implanted into the mPFC. The recording of the neuronal activity took place in the three-class oddball paradigm as well as in a passive two-class oddball paradigm with unfamiliar frequencies. Correct responding to the Target tone was accompanied by a higher amplitude of the ERP in comparison to the Standard and Distractor tones (p < 0.05). Target Miss, or incorrect responding to Distractor or Standard led to reduced, respectively enhanced peak latency. In the two-class oddball paradigm, the amplitude of the Distractor ERP was enhanced as compared to that after Standard (p < 0.05). ERPs derived from mPFC LFPs of rats show key characteristics similar to that derived from human EEGs. This model allows to investigate the processing of behaviorally important and irrelevant auditory stimuli in subcortical brain regions in a translational approach.