Cortex Brain Regions Research Articles

The Anti-obesity Agent d-norpseudoephedrine Protects Against Rotenone-induced Parkinson’s Disease in Mice

The effect of the ephedrine derivative D-norpseudoephedrine on rotenone-induced Parkinson’s disease in mice was studied. Mice received subcutaneous injections of rotenone (1.5 mg/kg, every other day for two weeks) and were treated with the vehicle, L-dopa (25 mg/kg) or pseudoephedrine at doses of 1.8, 5.4 and 10.8 mg/kg once daily orally. Brain levels of malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NO) were determined and histopathological study of the brain was done. Motor testing included stair, wire hanging and wood walking tests. Results indicated that ompared with vehicle controls, rotenone caused significant increases in brain MDA and NO along with GSH depletion. Rotenone impaired neuromuscular strength, and motor balance and coordination. There were also marked decrease in size and number of substantia nigra pigmented cells and deeply stained neurons and karyorrhexis in the cerebral cortex and hippocampus. Treatment with pseudoephedrine reduced brain MDA, NO and increased GSH levels and improved motor performance. Furthermore, pseudoephedrine prevented substantia nigra dopaminergic cell death and neurodegeneration in the cortex and hippocampus brain regions in a dose-dependent manner. These data suggest that pseudoephedrine might prove of benefit adjunctive therapy of Parkinson’s disease.

Neuroprotective Effect of N-acetylcysteine Against Monocrotophos-Induced Oxidative Stress in Different Brain Regions of Rats.

Monocrotophos (MCP) is systemic organophosphate insecticide used against crop pests. It is reported to cause mammalian toxicity through both acute and chronic exposure. In the present study, we have shown the protective role of N-acetylcysteine (NAC) against MCP-induced oxidative stress in frontal cortex, corpus striatum and hippocampus brain regions of rats. Male Albino Wistar rats were divided into control, NAC-treated, MCP and NAC + MCP-treated groups. An oral dose of MCP (0.9mg/kg b.wt) and NAC (200mg/kg b.wt) was administered for 28days. Results showed an increase in lipid peroxidation (LPO) and protein oxidation followed by decreased antioxidant enzymes after 28days of MCP exposure. Histopathological analysis showed that monocrotophos exposure caused neurodegenerative changes as evident by neurons with dystrophic changes in the form of shrunken hyperchromatic nuclei in all the regions of the rat brain. N-acetylcysteine supplementation to MCP-treated rats showed a reduction in oxidative stress and ameliorated cellular alterations in all of the three regions. The results of the study indicate that N-acetylcysteine offers neuroprotection by improving antioxidant response and decreasing oxidative stress in different regions of the rat brain.

The Neural Circuit Architecture of Social Hierarchy in Rodents and Primates.

Social status is recognized as a major determinant of social behavior and health among animals; however, the neural circuits supporting the formation and navigation of social hierarchies remain under extensive research. Available evidence suggests the prefrontal cortex is a keystone in this circuit, but upstream and downstream candidates are progressively emerging. In this review, we compare and integrate findings from rodent and primate studies to create a model of the neural and cellular networks supporting social hierarchies, both from a macro (i.e., circuits) to a micro-scale perspective (microcircuits and synapses). We start by summarizing the literature on the prefrontal cortex and other relevant brain regions to expand the current “prefrontal-centric” view of social hierarchy behaviors. Based on connectivity data we also discuss candidate regions that might inspire further investigation, as well as the caveats and strategies that have been used to further our understanding of the biological substrates underpinning social hierarchy and dominance.

Social motivation deficits in individuals with autism spectrum disorders

<p id=p00005>Autism spectrum disorder (ASD) is a neurodevelopmental disorder that originated from childhood, social deficits are core symptoms of ASD. Previous studies, from a information processing perspective, proposed that a deficit in social cognitive is the cause of social impairment. However, research showed that the lack of cognitive ability was not the only reason for the social deficits of individuals with ASD, but also closely related to the social motivation deficits. Social motivation theory suggests that social motivation deficits exist in the early life of individuals with ASD and affect their subsequent development. Studying the social motivation of individuals with ASD is of great value to explain the causes of their social deficits and find the direction of intervention in the future. Therefore, this study summarizes the specific behaviors and internal and external influencing factors of social motivation deficits in individuals with ASD. In the future, it is important to comprehensively consider these factors, to strengthen the integrated research on the social motivation theory of individuals with ASD, so as to accurately understand the social motivation deficits of individuals with ASD. <br/>Social motivation theory suggests that social motivation is a powerful driving force to guide individual’s social behavior. The theory also highlights that social behavior is mainly manifested in social orientation, social reward and social maintenance, so this paper firstly summarizes the related researches on the behavioral level of social motivation deficits in individuals with ASD, which are mainly reflected in the following three aspects: (1) The results of social orientation research show that individuals with ASD often show impaired attention to social stimuli, reduced direct gaze on the face, reduced gaze on the eyes, etc. On the one hand, this deficit is related to their abnormal face processing strategies; on the other hand, they may have difficulties in representing the intrinsic reward value of social stimuli; (2) The results of social reward research show that social reward stimulation has no significant incentive effect on individuals with ASD. They lack the ability to experience the happiness of social interaction, cant get happiness from interaction and lack the desire to help others, which is related to the abnormality of reward processing system (amygdala, ventral striatum, prefrontal cortex and other brain regions). (3) The results of social maintenance research show that individuals with ASD have few social maintenance strategies, they are not good at maintaining social relationships with others, do not actively show their own advantages, do not actively imitate others, and lack the desire and motivation to establish and maintain good relationships with others. <br/>Finally, because the research conclusions of social motivation deficits in individual with ASD are not completely consistent, this paper comprehensively and systematically analyzes the influencing factors of social motivation deficits, and finds that it includes internal factors and external factors. The internal factors are mainly reflected in individuals age, gender and physiological mechanism, while the external factors are mainly reflected in social communication environment, experimental stimulus materials, difficulty and nature of experimental tasks. In order to improve the credibility and effectiveness of the research on the social motivation of individuals with ASD, and fully and accurately grasp the characteristics of social motivation in individuals with ASD, in the future, it is important to study the social motivation deficits of individuals with ASD of different ages and genders, to optimize the experimental tasks, broaden the types of materials, further improve the experimental design, and to strengthen the integrated research on the social motivation theory of individuals with ASD, deeply explore the relationship among the behavioral, biological and evolutionary levels under this theory, and further analyze the relationship among the three behaviors of social motivation(social orientation, social reward and social maintenance).

Structural Covariance of the Ipsilesional Primary Motor Cortex in Subcortical Stroke Patients with Motor Deficits.

The analysis of structural covariance has emerged as a powerful tool to explore the morphometric correlations among broadly distributed brain regions. However, little is known about the interactions between the damaged primary motor cortex (M1) and other brain regions in stroke patients with motor deficits. This study is aimed at investigating the structural covariance pattern of the ipsilesional M1 in chronic subcortical stroke patients with motor deficits. High-resolution T1-weighted brain images were acquired from 58 chronic subcortical stroke patients with motor deficits (29 with left-sided lesions and 29 with right-sided lesions) and 50 healthy controls. Structural covariance patterns were identified by a seed-based structural covariance method based on gray matter (GM) volume. Group comparisons between stroke patients (left-sided or right-sided groups) and healthy controls were determined by a permutation test. The association between alterations in the regional GM volume and motor recovery after stroke was investigated by a multivariate regression approach. Structural covariance analysis revealed an extensive increase in the structural interactions between the ipsilesional M1 and other brain regions in stroke patients, involving not only motor-related brain regions but also non-motor-related brain regions. We also identified a slightly different pattern of structural covariance between the left-sided stroke group and the right-sided stroke group, thus indicating a lesion-side effect of cortical reorganization after stroke. Moreover, alterations in the GM volume of structural covariance brain regions were significantly correlated to the motor function scores in stroke patients. These findings indicated that the structural covariance patterns of the ipsilesional M1 in chronic subcortical stroke patients were induced by motor-related plasticity. Our findings may help us to better understand the neurobiological mechanisms of motor impairment and recovery in patients with subcortical stroke from different perspectives.

Effects of Synaptotagmin1 gene knockout on the behavior of mice

Objective: To study the effects of Synaptotagmin1 gene knockout (Syt1+/-) on emotional behavior in mice and explore its possible mechanisms. Methods: Five 8-week-old male Syt1+/-mice and five wild-type (WT) mice in the same litter were selected. The expressions of Syt1 in 6 mice brain regions of prelimbic cortex (PL), hippocampus (HIP), amygdala (AMY), accumbens nucleus (ACB), caudoputamen (CP) and ventral tegmental area (VTA) were detected by Immunofluorescence staining. Nine 8-week-old male Syt1+/-mice and ten WT mice were selected as controls. The anxiety-like behaviors of adult Syt1+/- mice and WT mice were detected by open field test, elevated plus maze test and forced swim test. In addition, five 8-week-old male Syt1+/-mice and five WT mice were selected to detect the glutamate content in prelimbic cortex, hippocampus and amygdala. Results: Compared with WT mice, the number of Syt1 positive cells in PL, HIP, AMY, ACB, CP and VTA were decreased significantly in Syt1+/- mice (P＜0.01); Syt1+/- mice had less total movement distance in open field test (P＜0.01), more preference for peripheral area (P＜0.01) and less desire to explore the central platform (P＜0.01), while Syt1+/- mice preferred to stay in a closed and safe environment (P＜0.01); the number (P＜0.05) and the time spent in open-arm explorations (P＜0.01) were reduced significantly; the immobile time of Syt1+/- mice was increased in the forced swim test (P＜0.01). Meanwhile, the concentration of glutamate in the amygdala of Syt1+/- mice was increased significantly (P＜0.01). Conclusion: Syt1 gene knockout leads to significant anxiety-like behavior in mice, which is deduced that related to the increase of glutamate content in the amygdala.

Rethinking “aggression” and impulsivity in bipolar disorder: Risk, clinical and brain circuitry features

BackgroundElevated aggression and impulsivity are implicated in Bipolar Disorder (BD); however, relationships between these behavioral constructs have not been clarified, which can lead to misconceptions with negative consequences including stigma and adverse outcomes including suicide. The study aimed to clarify brain-based distinctions between the two constructs and their associations to risk factors, symptoms and suicide thoughts and behaviors. MethodsSelf-rated Brown-Goodwin Aggression (BGA) and Barratt Impulsiveness Scale (BIS) scores were compared between adults with BD (n = 38, 74% female) and healthy controls (HC, n = 29, 64% female). Relationships were examined between BGA and BIS with childhood trauma questionnaire (CTQ), mood, comorbidities, and magnetic resonance imaging gray matter volume (GMV) assessments. ResultsIn BD, BGA and BIS total scores were both elevated and associated with childhood maltreatment (CM), particularly emotional CM, depression, substance use disorders (SUDs) and suicide attempts (SAs). BGA scores were increased by items corresponding to dysregulation of emotional and social behavior and associated with elevated mood states and suicide ideation and GMV decreases in bilateral orbitofrontal cortex and left posterior insula brain regions, previously associated with these behaviors and clinical features. BIS motor impulsiveness scores were associated with GMV decreases in anterior cingulate cortex implicated in mood and behavioral dyscontrol. Limitationsmodest sample size, self-reports ConclusionsThe findings suggest separable brain-based domains of dysfunction in BD of motor impulsiveness versus emotionally dysregulated feelings that are primarily self-directed. Both domains are associated with suicide behavior and modifiable risk factors of CM, depression and SUDs that could be targeted for prevention.

Neuroprotective Effects of Myrtenal in an Experimental Model of Dementia Induced in Rats.

There is growing attention on natural substances capable of stimulating the cholinergic system and of exerting antioxidant effects, as potential therapeutic agents in Alzheimer’s disease (AD). The aim of the present study is to evaluate the expected neuroprotective mechanisms of myrtenal (M) in an experimental model of dementia in rats. Dementia was induced in male Wistar rats by scopolamine (Sc) administration (0.1 mg/kg for 8 days and 20.0 mg/kg on day 9). The animals were divided into 5 groups (1) Controls; (2) Sc; (3) Sc + Myrtenal (40 mg/kg), (4) Sc + Galantamine (1 mg/kg); (5) Sc + Lipoic acid (30 mg/kg). Changes in recognition memory and habituation were evaluated via the Novel Object Recognition and Open Field tests. Acetylcholinesterase (AChE) activity, ACh levels, and changes in oxidative status of the brain were measured biochemically. The histological changes in two brain regions—cortex and hippocampus, were evaluated qualitatively and quantitatively. Myrtenal improved recognition memory and habituation, exerted antioxidant effects and significantly increased ACh brain levels. Histologically, the neuroprotective capacity of myrtenal was also confirmed. For the first time, we have demonstrated the neuroprotective potential of myrtenal in an experimental model of dementia. Our study provides proof-of-concept for the testing of myrtenal, in association with standard of care treatments, in patients affected by cognitive decline.

Alterations of Prefrontal-Posterior Information Processing Patterns in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a heterogeneous disorder characterized by different levels of repetitive and stereotypic behavior as well as deficits in social interaction and communication. In this current study, we explored the changes in cerebral neural activities in ASD. The purpose of this study is to investigate whether there exists a dysfunction of interactive information processing between the prefrontal cortex and posterior brain regions in ASD. We investigated the atypical connectivity and information flow between the prefrontal cortex and posterior brain regions in ASD utilizing the entropy connectivity (a kind of directional connectivity) method. Eighty-nine patients with ASD and 94 typical developing (TD) teenagers participated in this study. Two-sample t-tests revealed weakened interactive entropy connectivity between the prefrontal cortex and posterior brain regions. This result indicates that there exists interactive prefrontal-posterior underconnectivity in ASD, and this disorder might lead to less prior knowledge being used and updated. Our proposals highlighted that aforementioned atypical change might accelerate the deoptimization of brain networks in ASD.

A preliminary investigation of the effects of patellar displacement on brain activation and perceived pain in young females with patellofemoral pain

ObjectivesTo identify the neural substrates of a clinician-based test and associated pain perception in young female athletes with patellofemoral pain. DesignCross-sectional. MethodsFemales with patellofemoral pain (n = 14; 14.3 ± 3.2 years) completed a patella displacement test during brain functional magnetic resonance imaging. The neuroimaging protocol included 18 s of interspersed rest/test blocks during which an experimenter manually applied intermittent frontal plane stress to the patella during test blocks. Patients rated their pain unpleasantness and pain intensity immediately after testing using a visual analog scale. ResultsDuring the patella displacement test, increased activation was observed in previously identified sensorimotor and neural pain regions, including the primary and secondary somatosensory cortices, primary motor cortex, prefrontal cortex, cerebellum, and other cognitive-related brain regions (z's > 4.4, p's < 0.05). Furthermore, pain unpleasantness during the test was positively correlated with increased activation of the posterior cerebellum (z = 4.51, p = 0.02), which is involved in both motor and pain processing as well as cognitive and affective feedback. ConclusionsThese preliminary findings suggest that the posterior cerebellum may represent a critical modulator in the cognitive appraisal of pain in patellofemoral pain through cortico-cerebellar loops, which may have downstream effects on motor function. However further exploration of task-based functional connectivity between the posterior cerebellum and cortical regions is necessary to support these novel findings and associated interpretations.

Morphological diversity of single neurons in molecularly defined cell types

Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types1,2, yet our knowledge of its diversity remains limited. Here, to systematically examine complete single-neuron morphologies on a brain-wide scale, we established a pipeline encompassing sparse labelling, whole-brain imaging, reconstruction, registration and analysis. We fully reconstructed 1,741 neurons from cortex, claustrum, thalamus, striatum and other brain regions in mice. We identified 11 major projection neuron types with distinct morphological features and corresponding transcriptomic identities. Extensive projectional diversity was found within each of these major types, on the basis of which some types were clustered into more refined subtypes. This diversity follows a set of generalizable principles that govern long-range axonal projections at different levels, including molecular correspondence, divergent or convergent projection, axon termination pattern, regional specificity, topography, and individual cell variability. Although clear concordance with transcriptomic profiles is evident at the level of major projection type, fine-grained morphological diversity often does not readily correlate with transcriptomic subtypes derived from unsupervised clustering, highlighting the need for single-cell cross-modality studies. Overall, our study demonstrates the crucial need for quantitative description of complete single-cell anatomy in cell-type classification, as single-cell morphological diversity reveals a plethora of ways in which different cell types and their individual members may contribute to the configuration and function of their respective circuits.

Sex differences in the brain

ABSTRACT This special issue of Cognitive Neuroscience focuses on sex differences in the brain. Berchicci, Bianco, and Di Russo found ERP auditory cortex activity was larger in females than males during sound perception. Spets, Fritch, Thakral, & Slotnick reported greater fMRI activity during high- versus low-confidence spatial memory in males than females within the lateral prefrontal cortex and other brain regions. Using fMRI resting-state data, Murray, Maurer, Peechatka, Frederick, Kaiser, and Janes observed females spent more time in transient dorsal attention/occipital/sensory-motor network states and males spent more time in transient salience network states, and de Lacy, Kutz, and Calhoun found that brain dynamism (transitioning between brain states) was correlated with anxiety/depression in males and drive/novelty-seeking/self-control in females. Kurth, Gaser, and Luders predicted the sex of girls and boys with an 80.4% accuracy using a classifier based on anatomic (MRI) data. In a discussion paper, Spets and Slotnick conducted an fMRI meta-analysis that revealed greater male than female long-term memory activity in the lateral prefrontal cortex, visual processing regions, and the parahippocampal cortex, and argued against the claim there is reporting bias in sex-differences studies. In response to this discussion paper, commentaries were written by Cahill; de Lacy; Hausmann; McGlade, Rogowska, and Yurgelun-Todd; Sneider and Silveri; Tejavibulya and Scheinost; Wiersch and Weis; Young and Compère. It is hoped that these findings will help motivate a shift in the field to consider sex as a factor in cognitive neuroscience studies.

Altered Brain Functional Connectivity at Resting-State in Patients With Non-arteritic Anterior Ischemic Optic Neuropathy.

Purpose: To investigate the possible changes in functional connectivity (FC) in patients with non-arteritic anterior ischemic optic neuropathy (NAION) using resting-state functional MRI (fMRI).Methods: Thirty-one NAION patients and 31 healthy controls were recruited and underwent resting-state fMRI scans. Regions of interest (ROIs) were defined as bilateral Brodmann’s area 17 (BA17). FC analysis was performed between the ROIs and the rest of the brain regions, and the between group comparisons of FC were performed. We conducted correlation analysis between the FC changes and the clinical variables in NAION patients.Results: Compared with healthy controls, patients with NAION showed significantly decreased FC between the left BA17 and the right inferior frontal gyrus, left caudate nucleus. As for the right BA17, patients exhibited significantly increased FC with the left olfactory gyrus and decreased FC with the right superior frontal gyrus (SFG), right insula. Moreover, FC values between the right insula and the right BA17 were positively correlated with the right side of mean sensitivity in the central visual field (r = 0.52, P < 0.01) and negatively correlated with the right side of mean defect in the central visual field (r = −0.55, P < 0.01).Conclusion: Our study indicated that patients with NAION showed significantly abnormal functional reorganization between the primary visual cortex and several other brain regions not directly related to visual function, which supports that NAION may not only be an ophthalmic disease but also a neuro-ophthalmological disease.

Identification of Full-Length Wild-Type and Mutant Huntingtin Interacting Proteins by Crosslinking Immunoprecipitation in Mice Brain Cortex.

Background:Huntington’s disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein.Objective:Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington’s disease pathology.Methods:Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Interacting proteins were identified and quantified by label-free liquid chromatography-mass spectrometry (LC-MS/MS).Results:We identified 30 interactors specific for wild-type huntingtin, 14 interactors specific for mutant huntingtin and 14 shared interactors that interacted with both wild-type and mutant huntingtin, including known interactors such as F8a1/Hap40. Syt1, Ykt6, and Snap47, involved in vesicle transport and exocytosis, were among the proteins that interacted specifically with wild-type huntingtin. Various other proteins involved in energy metabolism and mitochondria were also found to associate predominantly with wild-type huntingtin, whereas mutant huntingtin interacted with proteins involved in translation including Mapk3, Eif3h and Eef1a2.Conclusion:Here we identified both shared and specific interactors of wild-type and mutant huntingtin, which are involved in different biological processes including exocytosis, vesicle transport, translation and metabolism. These findings contribute to the understanding of the roles that wild-type and mutant huntingtin play in a variety of cellular processes both in healthy conditions and Huntington’s disease pathology.

Isoformononetin, a dietary isoflavone protects against streptozotocin induced rat model of neuroinflammation through inhibition of NLRP3/ASC/IL-1 axis activation

AimsIsoformononetin (IFN), a methoxyl isoflavone present in most of human dietary supplements. However, being a highly potent antioxidant and anti-inflammatory molecule, its activity against neuronal oxidative stress and neuroinflammation has not been explored till now. The present study was inquested to assess the antioxidant, anti-apoptotic and anti-inflammatory activity of IFN against streptozotocin induced neuroinflammation in different brain regions of rat. Main methodsFour groups of animals were subjected to treatment as control, toxic control (STZ; single intracerebrovascular injection), third group (STZ + IFN; 20 mg/kg p.o.), fourth group (IFN) for 14 days. The different brain regions of rats were evaluated for inflammatory, apoptotic and biochemical antioxidant markers. The brain tissues were further assessed for gene expression, immunohistochemical and western blotting examination for localization of inflammasome cascade expression that plays a pivotal role in neuroinflammation. Key findingsThe modulation in oxidant/antioxidant status after exposure of STZ was significantly balanced after administration of IFN to rats. Further, IFN was also found to be an apoptotic agent as it modulates the apoptotic gene (Bax) and anti-apoptotic gene (BcL2) expression. IFN significantly curtailed the augmented protein expression of NLRP3, NLRP2, ASC, NFκBP65, IL-1β and caspase-1 due to STZ administration in cortex and hippocampus rat brain regions. SignificanceThe aforementioned results proclaim the neuroprotective functioning of IFN against STZ induced inflammation. IFN significantly prevents the neuroinflammation by decreasing the generation of ROS that reduces the activation of NLRP3/ASC/IL-1 axis thereby exerting neuroprotection as evidenced in rat model of STZ induced neuroninflammation.

Investigation of the Molecular Role of Brain-Derived Neurotrophic Factor in Alzheimer's Disease.

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a member of the neurotrophin family of growth factors that acts on both the central and peripheral nervous systems. BDNF is also well known for its cardinal role in normal neural maturation. It binds to at least two receptors at the cell surface known as tyrosine kinase B (TrkB) and p75NTR. Additional neurotrophins that are anatomically linked with BDNF include neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and nerve growth factor (NGF). It is evident that BDNF levels in patients with Alzheimer's disease (AD) are altered. AD is a progressive disorder and a form of dementia, where the mental function of an elderly person is disrupted. It is associated with a progressive decline in cognitive function, which mainly targets the thinking, memory, and behavior of the person. The degeneration of neurons occurs in the cerebral cortex region of brain. The two major sources responsible for neuronal degeneration are protein fragment amyloid-beta (Aβ), which builds up in the spaces between the nerve cells, known as plaques, disrupting the neuron signaling pathway and leading to dementia, and neurofibrillary tangles (NFTs), which are the twisted fibers of proteins that build up inside the cells. AD is highly prevalent, with recent data indicating nearly 5.8 million Americans aged 65 and older with AD in 2020, and with 80% of patients 75 and older. AD is recognized as the sixth leading cause of death in the USA, and its prevalence is predicted to increase exponentially in the coming years. As AD worsens over time, it becomes increasingly important to understand the exact pathophysiology, biomarkers, and treatment. In this article, we focus primarily on the controversial aspect of BDNF in AD, including its influence on various other proteins and enzymes and the current treatments associated with BDNF, along with future perspectives.

Therapeutic effects of astragaloside IV and Astragalus spinosus saponins against bisphenol A-induced neurotoxicity and DNA damage in rats.

BackgroundBisphenol A (BPA) is an endocrine disruptor to which humans are often subjected during daily life. This study aimed to investigate the ameliorative effect of astragaloside IV (ASIV) or saponins extracted from Astragalus spinosus (A. spinosus) against DNA damage and neurotoxic effects induced by BPA in prefrontal cortex (PFC), hippocampal and striatal brain regions of developing male rats.Materials and MethodsJuvenile PND20 (pre-weaning; age of 20 days) male Sprague Dawley rats were randomly and equally divided into four groups: control, BPA, BPA+ASIV and BPA+A. spinosus saponins groups. Bisphenol A (125 mg/kg/day) was administrated orally to male rats from day 20 (BPA group) and along with ASIV (80 mg/kg/day) (BPA+ASIV group) or A. spinosus saponin (100 mg/kg/day) (BPA+ A. spinosus saponins group) from day 50 to adult age day 117.ResultsIncreased level of nitric oxide (NO) and decreased level of glutamate (Glu), glutamine (Gln), glutaminase (GA) and glutamine synthetase (GS) were observed in the brain regions of BPA treated rats compared with the control. On the other hand, co-administration of ASIV or A. spinosus saponin with BPA considerably improved levels of these neurochemicals. The current study also revealed restoration of the level of brain derived neurotrophic factor (BDNF) and N-methyl-D-aspartate receptors (NR2A and NR2B) gene expression in BPA+ ASIV and BPA+A. spinosus saponins groups. The co-treatment of BPA group with ASIV or A. spinosus saponin significantly reduced the values of comet parameters as well as the intensity of estrogen receptors (ERs) immunoreactive cells and improved the histological alterations induced by BPA in different brain regions.ConclusionIt could be concluded that ASIV or A. spinosus saponins has a promising role in modulating the neurotoxicity and DNA damage elicited by BPA.

Characterization of the blood\u2013brain barrier in genetically diverse laboratory mouse strains

BackgroundGenetic variation in a population has an influence on the manifestation of monogenic as well as multifactorial disorders, with the underlying genetic contribution dependent on several interacting variants. Common laboratory mouse strains used for modelling human disease lack the genetic variability of the human population. Therefore, outcomes of rodent studies show limited relevance to human disease. The functionality of brain vasculature is an important modifier of brain diseases. Importantly, the restrictive interface between blood and brain—the blood–brain barrier (BBB) serves as a major obstacle for the drug delivery into the central nervous system (CNS). Using genetically diverse mouse strains, we aimed to investigate the phenotypic and transcriptomic variation of the healthy BBB in different inbred mouse strains.MethodsWe investigated the heterogeneity of brain vasculature in recently wild-derived mouse strains (CAST/EiJ, WSB/EiJ, PWK/PhJ) and long-inbred mouse strains (129S1/SvImJ, A/J, C57BL/6J, DBA/2J, NOD/ShiLtJ) using different phenotypic arms. We used immunohistochemistry and confocal laser microscopy followed by quantitative image analysis to determine vascular density and pericyte coverage in two brain regions—cortex and hippocampus. Using a low molecular weight fluorescence tracer, sodium fluorescein and spectrophotometry analysis, we assessed BBB permeability in young and aged mice of selected strains. For further phenotypic characterization of endothelial cells in inbred mouse strains, we performed bulk RNA sequencing of sorted endothelial cells isolated from cortex and hippocampus.ResultsCortical vessel density and pericyte coverage did not differ among the investigated strains, except in the cortex, where PWK/PhJ showed lower vessel density compared to NOD/ShiLtJ, and a higher pericyte coverage than DBA/2J. The vascular density in the hippocampus differed among analyzed strains but not the pericyte coverage. The staining patterns of endothelial arteriovenous zonation markers were similar in different strains. BBB permeability to a small fluorescent tracer, sodium fluorescein, was also similar in different strains, except in the hippocampus where the CAST/EiJ showed higher permeability than NOD/ShiLtJ. Transcriptomic analysis of endothelial cells revealed that sex of the animal was a major determinant of gene expression differences. In addition, the expression level of several genes implicated in endothelial function and BBB biology differed between wild-derived and long-inbred mouse strains. In aged mice of three investigated strains (DBA/2J, A/J, C57BL/6J) vascular density and pericyte coverage did not change—expect for DBA/2J, whereas vascular permeability to sodium fluorescein increased in all three strains.ConclusionsOur analysis shows that although there were no major differences in parenchymal vascular morphology and paracellular BBB permeability for small molecular weight tracer between investigated mouse strains or sexes, transcriptomic differences of brain endothelial cells point to variation in gene expression of the intact BBB. These baseline variances might be confounding factors in pathological conditions that may lead to a differential functional outcome dependent on the sex or genetic polymorphism.

Fourier Transform Infrared Imaging-A Novel Approach to Monitor Bio Molecular Changes in Subacute Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) can be defined as a disorder in the function of the brain after a bump, blow, or jolt to the head, or penetrating head injury. Mild traumatic brain injury (mTBI) can cause devastating effects, such as the initiation of long-term neurodegeneration in brain tissue. In the current study, the effects of mTBI were investigated on rat brain regions; cortex (Co) and corpus callosum (CC) after 24 h (subacute trauma) by Fourier transform infrared (FTIR) imaging and immunohistochemistry (IHC). IHC studies showed the formation of amyloid-β (Aβ) plaques in the cortex brain region of mTBI rats. Moreover, staining of myelin basic protein presented the shearing of axons in CC region in the same group of animals. According to FTIR imaging results, total protein and lipid content significantly decreased in both Co and CC regions in mTBI group compared to the control. Due to this significant decrease in both lipid and protein content, remarkable consistency in lipid/protein band ratio in mTBI and control group, was observed. Significant decrease in methyl content and a significant increase in olefinic content were observed in Co and CC regions of mTBI rat brain tissues. Classification amongst distinguishable groups was performed using principal component analysis (PCA) and hierarchical clustering (HCA). This study established the prospective of FTIR imaging for assessing biochemical changes due to mTBI with high sensitivity, precision and high-resolution.

Characterization of Alzheimer's Disease‐like Neuropathology in Duchenne Muscular Dystrophy Using the D2 mdx Mouse Model

Duchenne Muscular Dystrophy (DMD) is a progressive muscle wasting disorder which affects approximately 1 in 3500 male births and is caused by a mutation in the dystrophin gene. Although most research focuses on the role of dystrophin in skeletal and cardiac muscle, dystrophin is also expressed in the brain, specifically in memory-associated brain regions like the hippocampus and cortex. Furthermore, patients with DMD and mdx mice (rodent model of DMD) exhibit significant memory and learning impairments, implicating dystrophin loss in neurodegeneration. A recent study found patients with DMD had higher serum amyloid-β42, with this marker being heavily associated with cognitive impairments and Alzheimer's disease pathology. The purpose of this study was to characterize the neuropathology associated with DMD, focusing on markers of amyloidogenesis and synaptic function, in a preclinical mdx mouse model. Male mdx and age matched (8-9 weeks old) wild-type (DBA-2J) mice were purchased from Jackson laboratories (n = 12 per group). Novel object recognition testing (NORT) was performed to determine cognitive function. Prefrontal cortex and hippocampus brain regions were extracted for analysis. NORT testing demonstrated that mdx mice had reduced exploration time of the novel object (WT 35.2 sec vs mdx 18.7 sec; p = 0.02) and a lower exploration index (-25%, p < 0.05) compared to WT mice. Western blot analysis revealed higher soluble APP β (+40%) and total APP (+20%) in the prefrontal cortex of mdx mice compared to WT, and lower soluble APP α (-30%) fragment in the hippocampus (p <0.05). Furthermore, PSD95 content was nearly 2-fold higher in the prefrontal cortex of mdx mice compared to WT (p <0.05). This study provides novel information about the cellular pathways associated with memory impairment with DMD. Specifically, we show a shift towards amyloidogenesis in the prefrontal cortex and hippocampus brain regions of mdx mice, suggesting the possibility of similar pathogenesis to Alzheimer's disease. These changes are accompanied by reduced performance in the NORT test. Importantly, our results demonstrate that these changes occur at a relatively young age in D2 mdx mice, similar to what is observed in patients with DMD.