Discrete Brain Regions Research Articles

In Utero Exposure to Di-n-butyl Phthalate Causes Modulation in Neurotransmitter System of Wistar Rats: A Multigenerational Assessment.

Neuroendocrine regulation is disrupted by di-n-butyl phthalate (DBP) when exposure occurs during the critical periods of fetal development, which can lead to neurological disorders. To evaluate the toxic potential of DBP, it is necessary to conduct teratological studies, which could determine impacts on the development of the fetus. The present study was designed to understand the sequelae of neuroendocrine regulation in one-month-old pups when rats were exposed to DBP (F1-F3) in utero and during lactation. The rats received DBP (500mg/kg BW/day) dissolved in olive oil through oral gavage from gestation day 6 to postnatal day 30, while the control group received the olive oil (vehicle) during the same timeline. Following the exposure, thyroid profile and estradiol, which were measured at GD-19, exhibited a significant decrease (P < 0.05) in dams (F0-F2). The exposure resulted in developmental outcomes, including underdeveloped fetuses, and a notable number of resorptions in experimental rats. The one-month-old pups were assessed for serum thyroid profile and testosterone and neurotransmitters in discrete brain regions, cerebral cortex, cerebellum, and hippocampus for up to three generations. The levels of dopamine and cortisol showed a significant increase (P < 0.05), but serotonin levels decreased when examined in distinct brain regions of the experimental group as compared to the control. DBP, which is considered an endocrine disruptor, had the most impact on the third generation in this study, leading to a significant decrease in testosterone levels. In summary, in utero exposure to DBP impaired the neuroendocrine system and had an antiandrogenic effect in the three successive generations.

18 kDa Translocator protein (TSPO) is upregulated in rat brain after peripheral nerve injury and downregulated by diroximel fumarate

Neuroimmune signaling is a key process underlying neuropathic pain. Clinical studies have demonstrated that 18 kDa translocator protein (TSPO), a putative marker of neuroinflammation, is upregulated in discrete brain regions of patients with chronic pain. However, no preclinical studies have investigated TSPO dynamics in the brain in the context of neuropathic pain and in response to analgesic treatments. We used positron emission tomography-computed tomography (PET-CT) and [18F]-PBR06 radioligand to measure TSPO levels in the brain across time after chronic constriction injury (CCI) of the sciatic nerve in both male and female rats. Up to 10 weeks post-CCI, TSPO expression was increased in discrete brain regions, including medial prefrontal cortex, somatosensory cortex, insular cortex, anterior cingulate cortex, motor cortex, ventral tegmental area, amygdala, midbrain, pons, medulla, and nucleus accumbens. TSPO was broadly upregulated across these regions at 4 weeks post CCI in males, and 10 weeks in females, though there were regional differences between the sexes. Using immunohistochemistry, we confirmed TSPO expression in these regions. We further demonstrated that TSPO was upregulated principally in microglia in the nucleus accumbens core, and astrocytes and endothelial cells in the nucleus accumbens shell. Finally, we tested whether TSPO upregulation was sensitive to diroximel fumarate, a drug that induces endogenous antioxidants via nuclear factor E2-related factor 2 (Nrf2). Diroximel fumarate alleviated neuropathic pain and reduced TSPO upregulation. Our findings indicate that TSPO is upregulated over the course of neuropathic pain development and is resolved by an antinociceptive intervention in animals with peripheral nerve injury.

Assessing the newly proposed MRI criteria for diagnosing sporadic Creutzfeldt-Jakob disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a frequent differential diagnostic consideration in patients with rapidly progressive dementia (RPD). Fortunately, in the last 2 decades there has been substantial cumulative improvements in sCJD biomarkers, particularly those based on imaging and cerebrospinal fluid (CSF) interrogation. Brain MRI is a very frequently employed investigation in patients with RPD, often utilized quite early in the evaluation and thereby offering a potentially key role in prompting initial concerns for sCJD. Extant conventional MRI criteria for sCJD diagnosis are relatively stringent, requiring fluid attenuated inversion recovery (FLAIR) or diffusion weighted imaging (DWI) high signal changes in 2 or more cortical regions (excluding frontal) or in both the caudate and putamen. Challenging these conventional criteria, a recent publication described improved sensitivity and unchanged specificity if MRI criteria were arguably less rigorous, requiring DWI high signal changes in only 1 or more of 7 discrete brain regions: frontal, parietal, occipital or temporal cortices, as well as the caudate, putamen or thalamus. The aim of the current study was to test the diagnostic performance of this proposed change in MRI criteria in the Australian context and compare it with conventional criteria, as well as 2 other stringent sets of criteria, predicting that a similar improved sensitivity with unchanged specificity would be observed when the proposed criteria were utilized. Sixty-five definite sCJD cases were compared with 63 age- and sex-matched controls. Radiological review of all MRIs applying the different sets of MRI criteria was undertaken by a blinded neuroradiologist, very experienced in CJD interpretation, with independent assessment of 71 MRIs performed by a second blinded neuroradiologist less experienced in sCJD imaging findings. Our study found the sensitivity of the recently proposed MRI criteria (92.3%) to be comparable to that originally reported (90-95%) and also equivalent to the conventional MRI diagnostic criteria (92.3%), while the specificities were also quite similar between the conventional MRI criteria (87.3%) and proposed criteria (85.7%), with the latter lower than previously reported. Negative predictive values and positive predictive values were also very similar between the conventional and proposed MRI criteria. Other MRI criteria assessed were associated with unacceptably low sensitivity for clinical use. Inter-rater reliability as assessed by intra-class correlation coefficients (ICC) revealed moderate reliability for the conventional and proposed MRI criteria, modestly better in the former and when the frontal lobe was retained versus excluded in comparisons.

Lineage-specific changes in mitochondrial properties during neural stem cell differentiation.

Neural stem cells (NSCs) reside in discrete regions of the adult mammalian brain where they can differentiate into neurons, astrocytes, and oligodendrocytes. Several studies suggest that mitochondria have a major role in regulating NSC fate. Here, we evaluated mitochondrial properties throughout NSC differentiation and in lineage-specific cells. For this, we used the neurosphere assay model to isolate, expand, and differentiate mouse subventricular zone postnatal NSCs. We found that the levels of proteins involved in mitochondrial fusion (Mitofusin [Mfn] 1 and Mfn 2) increased, whereas proteins involved in fission (dynamin-related protein 1 [DRP1]) decreased along differentiation. Importantly, changes in mitochondrial dynamics correlated with distinct patterns of mitochondrial morphology in each lineage. Particularly, we found that the number of branched and unbranched mitochondria increased during astroglial and neuronal differentiation, whereas the area occupied by mitochondrial structures significantly reduced with oligodendrocyte maturation. In addition, comparing the three lineages, neurons revealed to be the most energetically flexible, whereas astrocytes presented the highest ATP content. Our work identified putative mitochondrial targets to enhance lineage-directed differentiation of mouse subventricular zone-derived NSCs.

Age-related trajectories of the development of social cognition.

Age-related trajectories of intrinsic functional connectivity (iFC), which represent the interconnections between discrete regions of the human brain, for processes related to social cognition (SC) provide evidence for social development through neural imaging and can guide clinical interventions when such development is atypical. However, due to the lack of studies investigating brain development over a wide range of ages, the neural mechanisms of SC remain poorly understood, although considerable behavior-related evidence is available. The present study mapped vortex-wise iFC features between SC networks and the entire cerebral cortex by using common functional networks, creating the corresponding age-related trajectories. Three networks [moral cognition, theory of mind (ToM), and empathy] were selected as representative SC networks. The Enhanced Nathan Kline Institute-Rockland Sample (NKI-RS, N = 316, ages 8-83 years old) was employed delineate iFC characteristics and construct trajectories. The results showed that the SC networks display unique and overlapping iFC profiles. The iFC of the empathy network, an age-sensitive network, with dorsal attention network was found to exhibit a linear increasing pattern, that of the ventral attention network was observed to exhibit a linear decreasing pattern, and that of the somatomotor and dorsal attention networks was noted to exhibit a quadric-concave iFC pattern. Additionally, a sex-specific effect was observed for the empathy network as it exhibits linear and quadric sex-based differences in iFC with the frontoparietal and vision networks, respectively. The iFC of the ToM network with the ventral attention network exhibits a pronounced quadric-convex (inverted U-shape) trajectory. No linear or quadratic trajectories were noted in the iFC of the moral cognition network. These findings indicate that SC networks exhibit iFC with both low-level (somatomotor, vision) and high-level (attention and control) networks along specific developmental trajectories. The age-related trajectories determined in this study advance our understanding of the neural mechanisms of SC, providing valuable references for identification and intervention in cases of development of atypical SC.

Prosaposin maintains adult neural stem cells in a state associated with deep quiescence

In most vertebrates, adult neural stem cells (NSCs) continuously give rise to neurons in discrete brain regions. A critical process for maintaining NSC pools over long periods of time in the adult brain is NSC quiescence, a reversible and tightly regulated state of cell-cycle arrest. Recently, lysosomes were identified to regulate the NSC quiescence-proliferation balance. However, it remains controversial whether lysosomal activity promotes NSC proliferation or quiescence, and a finer influence of lysosomal activity on NSC quiescence duration or depth remains unexplored. Using RNA sequencing and pharmacological manipulations, we show that lysosomes are necessary for NSC quiescence maintenance. In addition, we reveal that expression of psap, encoding the lysosomal regulator Prosaposin, is enriched in quiescent NSCs (qNSCs) that reside upstream in the NSC lineage and display a deep/long quiescence phase in the adult zebrafish telencephalon. We show that shRNA-mediated psap knockdown increases the proportion of activated NSCs (aNSCs) as well as NSCs that reside in shallower quiescence states (signed by ascl1a and deltaA expression). Collectively, our results identify the lysosomal protein Psap as a (direct or indirect) quiescence regulator and unfold the interplay between lysosomal function and NSC quiescence heterogeneities.

Abstract 37: The Brain Care Score and Neuroimaging Markers in Asymptomatic Individuals in the UK Biobank

The 21-point Brain Care Score (BCS) is a novel tool designed to motivate individuals and care providers to take action to reduce the risk of stroke and dementia by motivating lifestyle changes (Fig 1). In this study we aimed to assess if the BCS is also associated with brain changes on MRI in people who have not yet developed dementia or stroke. Methods: This study was conducted within the MRI substudy of the longitudinal cohort study UK Biobank. The assessed MRI neuroimaging markers included: brain volume, white matter hyperintensities (WMH) volume, fractional anisotropy (FA) and mean diffusivity (MD). FA/MD metrics were calculated as the average across 48 discrete brain regions. We used multivariable linear regression to test for association between the BCS computed using baseline data (2006-2010) and neuroimaging markers, measured both during first (2014+) and repeat (2019+) MRI assessments. Results: There were 34,772 study participants with MRIs and available BCS data (mean age 55, 53% female). Every five-point increase in the BCS was associated with an 11% increase in brain volume (Beta 0.11, SE 0.01), a 26% reduction in WMH volume (Beta -0.26, SE 0.01), a 13% increase in average FA (Beta 0.13, SE 0.02), and a 9% decrease in average MD (Beta -0.09, SE 0.01). There were 3,778 study participants with first and repeat MRI (mean age 53, 53% female). Comparing the first and repeat imaging assessments, every five-point increase in baseline BCS was associated with a slower growth in WMH volume (Beta -0.08, SE 0.03) and a slower reduction in average FA (Beta 0.11, SE 0.03). Discussion: Among middle-aged adults without dementia or stroke, a higher BCS is strongly associated with better neuroimaging brain health profiles and slower rates of brain health decline. Given that the neuroimaging markers evaluated in our study are recognized risk factors that precede stroke and dementia by many years, our results support the BCS is a promising tool for early intervention to prevent these conditions.

Brain antioxidant status and gene expressions of nicotinic and dopamine receptors are improved by black seed oil administration in cigarette smoke or nicotine vapour-exposed rats.

Smoking is associated with dysregulation of the antioxidant system and addiction. This study sought to ascertain the effect of Nigella Sativa (NS) oil on the antioxidant system, nicotine/tobacco addiction as well as the expressions of α4β2 nicotinic (nAChR) and dopamine type-2 (DRD2) receptors in selected brain regions of the rat. Thirty male Sprague-Dawley rats were divided into 6 groups comprising of vehicle-treated control, NS oil only, Smoke only, Smoke + NS oil, Nicotine only and Nicotine + NS oil. Animals were passively exposed to cigarette smoke or nicotine vapour for 12 weeks, however, NS oil treatment commenced from 9th-12th week of the experimental duration. Nicotine vapour and cigarette smoke-induced increase in cotinine level were significantly ameliorated by NS treatment. Cigarette smoke or nicotine vapour exposure significantly (p<0.05) decreased the level of antioxidant enzymes while increasing malondialdehyde level in the brain homogenates of the rats. Administration of NS oil significantly (p<0.05) reversed the reduced antioxidant level. Cigarette-smoke also significantly increased α4-nAChR expression in the frontal cortex and olfactory bulb compared to control. Nicotine vapour significantly increased DRD2 expression only in the olfactory cortex. NS oil administration reduced both the cigarette-smoke-induced increase in α4-nAChR and nicotine vapour-induced increase in DRD2 gene expression only in the olfactory cortex. Findings from this study suggest that NS oil improves brain antioxidant status while ameliorating nicotine vapour and cigarette smoke addiction through down-regulation of α4-nAChR and DRD2 gene expressions in discrete brain regions in Sprague-Dawley rats.

Region‐Specific Associations of Human Astrocytic Endfoot Genes with Alzheimer’s Disease Neuropathology and Cognitive Decline

AbstractBackgroundWe completed a well‐powered bulk transcriptomic analysis of the astrocytic water channel aquaporin‐4 (AQP4) and related glymphatic molecules and discovered significant associations with Alzheimer’s disease (AD) neuropathological and cognitive outcomes. Genes included AQP4 and dystrophin‐associated complex components, namely DMD, DTNA, DAG1, and SNTA1, which encode proteins responsible for anchoring the AQP4 channel to the astrocytic endfoot membrane.MethodLeveraging regional brain RNA sequencing from the ROS/MAP dataset (Table 1), we determined the effects of transcript‐level variation on neuropathological outcomes at autopsy and longitudinal cognition using multiple linear regression models and mixed effects models, respectively. Discrete brain regions included: the dorsolateral prefrontal cortex (DLPFC, N = 921), caudate nucleus (CN, N = 705), and posterior cingulate cortex (PCC, N = 516). Square‐root transformed neuropathological measures of amyloid and tau burden at autopsy were quantified using immunohistochemistry. Cognitive performance was assessed longitudinally with global cognition calculated as a composite score derived from 19 neuropsychological tests. All model covariates included age at death, sex, educational attainment, and post‐mortem interval. Longitudinal models also included latency to death and the fixed and random effect of interval between current and last visit.ResultHigher AQP4 expression in the DLPFC related to higher amyloid pathology (β = 0.21, P.fdr = 0.04). Similarly, higher DTNA expression was associated with higher tau burden (βDLPFC = 0.36, P.fdrDLPFC = 0.008) and a faster rate of cognitive decline (βDLPFC = ‐0.036, P.fdrDLPFC = 0.0004; βPCC = ‐0.037, P.fdrPCC = 0.02). Higher SNTA1 in the CN related to a faster rate of cognitive decline (β = ‐0.038, P.fdr = 0.03). A summary of significant associations is presented in Table 2 and select plots are provided in Figure 2. AQP4, DTNA, and SNTA1 showed comparable associations with clinical AD in independent datasets within the AMP‐AD project (https://agora.adknowledgeportal.org/).ConclusionOur results indicate that gene expression at the AQP4‐dystrophin axis relates to both AD neuropathology and cognition, particularly in the prefrontal cortex. Future analyses will incorporate single‐nucleus measures of gene expression and cell‐type deconvolution to clarify cell‐type specific contributions in this pathway. Together, these results highlight a set of genes relevant to glymphatic function that should be prioritized for future mechanistic studies.

Interaction of interictal epileptiform activity with sleep spindles is associated with cognitive deficits and adverse surgical outcome in pediatric focal epilepsy.

Temporal coordination between oscillations enables intercortical communication and is implicated in cognition. Focal epileptic activity can affect distributed neural networks and interfere with these interactions. Refractory pediatric epilepsies are often accompanied by substantial cognitive comorbidity, but mechanisms and predictors remain mostly unknown. Here, we investigate oscillatory coupling across large-scale networks in the developing brain. We analyzed large-scale intracranial electroencephalographic recordings in children with medically refractory epilepsy undergoing presurgical workup (n = 25, aged 3-21 years). Interictal epileptiform discharges (IEDs), pathologic high-frequency oscillations (HFOs), and sleep spindles were detected. Spatiotemporal metrics of oscillatory coupling were determined and correlated with age, cognitive function, and postsurgical outcome. Children with epilepsy demonstrated significant temporal coupling of both IEDs and HFOs to sleep spindles in discrete brain regions. HFOs were associated with stronger coupling patterns than IEDs. These interactions involved tissue beyond the clinically identified epileptogenic zone and were ubiquitous across cortical regions. Increased spatial extent of coupling was most prominent in older children. Poor neurocognitive function was significantly correlated with high IED-spindle coupling strength and spatial extent; children with strong pathologic interactions additionally had decreased likelihood of postoperative seizure freedom. Our findings identify pathologic large-scale oscillatory coupling patterns in the immature brain. These results suggest that such intercortical interactions could predict risk for adverse neurocognitive and surgical outcomes, with the potential to serve as novel therapeutic targets to restore physiologic development.

Spatial transcriptomics reveals unique gene expression changes in different brain regions after sleep deprivation

Sleep deprivation has far-reaching consequences on the brain and behavior, impacting memory, attention, and metabolism. Previous research has focused on gene expression changes in individual brain regions, such as the hippocampus or cortex. Therefore, it is unclear how uniformly or heterogeneously sleep loss affects the brain. Here, we use spatial transcriptomics to define the impact of a brief period of sleep deprivation across the brain in male mice. We find that sleep deprivation induced pronounced differences in gene expression across the brain, with the greatest changes in the hippocampus, neocortex, hypothalamus, and thalamus. Both the differentially expressed genes and the direction of regulation differed markedly across regions. Importantly, we developed bioinformatic tools to register tissue sections and gene expression data into a common anatomical space, allowing a brain-wide comparison of gene expression patterns between samples. Our results suggest that distinct molecular mechanisms acting in discrete brain regions underlie the biological effects of sleep deprivation.

Use of an immunocapture device to detect cytokine release in discrete brain regions.

Use of an immunocapture device to detect cytokine release in discrete brain regions.

Eastern Equine Encephalitis Virus Diversity in Massachusetts Patients, 1938-2020.

Eastern equine encephalitis virus (EEEV) is a relatively little-studied alphavirus that can cause devastating viral encephalitis, potentially leading to severe neurological sequelae or death. Although case numbers have historically been low, outbreaks have been increasing in frequency and scale since the 2000 s. It is critical to investigate EEEV evolutionary patterns, especially within human hosts, to understand patterns of emergence, host adaptation, and within-host evolution. To this end, we obtained formalin-fixed paraffin-embedded tissue blocks from discrete brain regions from five contemporary (2004-2020) patients from Massachusetts, confirmed the presence of EEEV RNA by in situ hybridization (ISH) staining, and sequenced viral genomes. We additionally sequenced RNA from scrapings of historical slides made from brain sections of a patient in the first documented EEE outbreak in humans in 1938. ISH staining revealed the presence of RNA in all contemporary samples, and quantification loosely correlated with the proportion of EEEV reads in samples. Consensus EEEV sequences were generated for all six patients, including the sample from 1938; phylogenetic analysis using additional publicly available sequences revealed clustering of each study sample with like sequences from a similar region, whereas an intrahost comparison of consensus sequences between discrete brain regions revealed minimal changes. Intrahost single nucleotide variant (iSNV) analysis of four samples from two patients revealed the presence of tightly compartmentalized, mostly nonsynonymous iSNVs. This study contributes critical primary human EEEV sequences, including a historic sequence as well as novel intrahost evolution findings, contributing substantially to our understanding of the natural history of EEEV infection in humans.

Loss of normal Alzheimer's disease-associated Presenilin 2 function alters antiseizure medicine potency and tolerability in the 6-Hz focal seizure model.

Patients with early-onset Alzheimer's disease (EOAD) experience seizures and subclinical epileptiform activity, which may accelerate cognitive and functional decline. Antiseizure medicines (ASMs) may be a tractable disease-modifying strategy; numerous ASMs are marketed with well-established safety. However, little information is available to guide ASM selection as few studies have rigorously quantified ASM potency and tolerability in traditional seizure models in rodents with EOAD-associated risk factors. Presenilin 2 (PSEN2) variants evoke EOAD, and these patients experience seizures. This study thus established the anticonvulsant profile of mechanistically distinct ASMs in the frontline 6-Hz limbic seizure test evoked in PSEN2-knockout (KO) mice to better inform seizure management in EOAD. The median effective dose (ED50) of prototype ASMs was quantified in the 6-Hz test in male and female PSEN2-KO and wild-type (WT) C57BL/6J mice (3-4 months old). Minimal motor impairment (MMI) was assessed to estimate a protective index (PI). Immunohistological detection of cFos established the extent to which 6-Hz stimulation activates discrete brain regions in KO vs. WT mice. There were significant genotype-related differences in the potency and tolerability of several ASMs. Valproic acid and levetiracetam were significantly more potent in male KO than in WT mice. Additionally, high doses of valproic acid significantly worsened MMI in KO mice. Conversely, carbamazepine was significantly less potent in female KO vs. WT mice. In both male and female KO mice vs. WTs, perampanel and lamotrigine were equally potent. However, there were marked genotype-related shifts in PI of both carbamazepine and perampanel, with KO mice exhibiting less MMI at the highest doses tested. Gabapentin was ineffective against 6-Hz seizures in KO mice vs. WTs without MMI changes. Neuronal activation 90 min following 6-Hz stimulation was significantly increased in the posterior parietal association cortex overlying CA1 and in the piriform cortex of WT mice, while stimulation-induced increases in cFos immunoreactivity were absent in KO mice. Acute ASM potency and tolerability in the high-throughput 6-Hz test may be significantly altered with loss of normal PSEN2 function. Seizures in discrete EOAD populations may benefit from precisely selected medicines optimized for primary ASM pharmacological mechanisms.

Cajanus cajan (L) Millsp. seed extract ameliorates scopolamine-induced amnesia through increase in antioxidant defense mechanisms and cholinergic neurotransmission.

Decline in cholinergic function and oxidative/nitrosative stress play a central role in Alzheimer's disease (AD). Previous quantitative HPLC profiling analysis has revealed the presence of Pinostrobin, formononetin, vitexin and other neuroprotective flavonoids in Cajanus cajan seed extract. This study was designed to investigate the protective action of Cajanus cajan ethanol seed extract (CC) on learning and memory functions using scopolamine mouse model of amnesia. Materials and methods: Adult mice were pretreated with CC (50, 100, or 200mg/kg, p.o) or vehicle (10ml/kg, p.o) for 16 days consecutively. Scopolamine, a competitive muscarinic cholinergic receptor antagonist (1mg/kg, i.p.) was given an hour after CC pretreatment from days 3 to 16. The mice were subjected to behavioural tests from day 11 (open field test (OFT)/ Y-maze test (YMT) and Morris water maze task (MWM) from days 12-16. Animals were euthanized 1h after behavioral test on day 16 and discrete brain regions isolated for markers of oxidative stress and cholinergic signaling. Molecular docking analysis was undertaken to predict the possible mechanism(s) of CC-induced anti-amnesic action. pre-administration of CC significantly reversed working memory and learning deficits caused by scopolamine in YMT and MWM tests, respectively. Moreover, CC prevented scopolamine-induced oxidative and nitrosative stress radicals in the hippocampus evidenced in significant increase in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities with a marked decrease in malondialdehyde (MDA) production, as well as significant inhibition of hippocampal scopolamine-induced increase in acetylcholinesterase activity by CC. The molecular docking analysis showed that out of the 19 compounds, the following had the highest binding affinity; Pinostrobin (-8.7 Kcal/mol), friedeline (-7.5kCal/mol), and lupeol (-8.2 Kcal/mol), respectively, to neuronal muscarinic M1 acetylcholine receptor, α7 nicotinic acetylcholine receptor and amyloid beta peptide binding pockets, which further supports the ability of CC to enhance neuronal cholinergic signaling and possible inhibition of amyloid beta aggregation. This study showed that Cajanus cajan seeds extract improved working memory and learning through enhancement of cholinergic signaling, antioxidant capacity and reduction in amyloidogenesis.

Commentary on "Repeated ethanol exposure and withdrawal alters angiotensin-converting enzyme 2 expression in discrete brain regions: Implications for SARS-CoV-2 neuroinvasion".

Alcohol: Clinical and Experimental ResearchAccepted Articles COMMENTARY Commentary on “Repeated ethanol exposure and withdrawal alters angiotensin-converting enzyme 2 expression in discrete brain regions: Implications for SARS-CoV-2 neuroinvasion” Sulie L. Chang, Corresponding Author Sulie L. Chang [email protected] orcid.org/0000-0003-3865-4280 Institute of NeuroImmune Pharmacology, South Orange, NJ, USA Department of Biological Sciences, Seton Hall University, South Orange, NJ, USA Correspondence Sulie L. Chang, Institute of NeuroImmune Pharmacology South Orange, NJ, USA, Department of Biological Sciences, Seton Hall University, South Orange, NJ, USA. Email: [email protected]Search for more papers by this authorJonathan Zhang, Jonathan Zhang Institute of NeuroImmune Pharmacology, South Orange, NJ, USA Department of Biological Sciences, Seton Hall University, South Orange, NJ, USASearch for more papers by this author Sulie L. Chang, Corresponding Author Sulie L. Chang [email protected] orcid.org/0000-0003-3865-4280 Institute of NeuroImmune Pharmacology, South Orange, NJ, USA Department of Biological Sciences, Seton Hall University, South Orange, NJ, USA Correspondence Sulie L. Chang, Institute of NeuroImmune Pharmacology South Orange, NJ, USA, Department of Biological Sciences, Seton Hall University, South Orange, NJ, USA. Email: [email protected]Search for more papers by this authorJonathan Zhang, Jonathan Zhang Institute of NeuroImmune Pharmacology, South Orange, NJ, USA Department of Biological Sciences, Seton Hall University, South Orange, NJ, USASearch for more papers by this author First published: 26 May 2023 https://doi.org/10.1111/acer.15122 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/acer.15122. AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Accepted ArticlesAccepted, unedited articles published online and citable. The final edited and typeset version of record will appear in the future. RelatedInformation

A Brief History of Transcranial Magnetic Stimulation

A Brief History of Transcranial Magnetic Stimulation

Repeated ethanol exposure and withdrawal alters angiotensin-converting enzyme 2 expression in discrete brain regions: Implications for SARS-CoV-2 neuroinvasion.

People with alcohol use disorder (AUD) may be at higher risk for COVID-19. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are required for cellular entry by SARS-CoV-2, but information on their expression in specific brain regions after alcohol exposure is limited. We sought to clarify how chronic alcohol exposure affects ACE2 expression in monoaminergic brainstem circuits and other putative SARS-CoV-2 entry points. Brains were examined for ACE2 using immunofluorescence after 4 weeks of chronic intermittent ethanol (CIE) vapor inhalation. We also examined TMPRSS2, Cathepsin L, and ADAM17 by Western blot and RAS pathway mediators and pro-inflammatory markers via RT-qPCR. ACE2 was increased in most brain regions following CIE including the olfactory bulb (OB), hypothalamus (HT), raphe magnus (RMG), raphe obscurus (ROB), locus coeruleus (LC), and periaqueductal gray (PAG). We also observed increased colocalization of ACE2 with monoaminergic neurons in brainstem nuclei. Moreover, soluble ACE2 (sACE2) was elevated in OB, HT, and LC. The increase in sACE2 in OB and HT was accompanied by upregulation of ADAM17, an ACE2 sheddase, while TMPRSS2 increased in HT and LC. Cathepsin L, an endosomal receptor involved in viral entry, was also increased in OB. Alcohol can increase Angiotensin II, which triggers a pro-inflammatory response that may upregulate ACE2 via activation of RAS pathway receptors AT1R/AT2R. ACE2 then metabolizes Angiotensin II to Angiotensin (1-7) and provokes an anti-inflammatory response via MAS1. Accordingly, we report that AT1R/AT2R mRNA decreased in OB and increased in the LC, while MAS1 mRNA increased in both OB and LC. Other mRNAs for pro-inflammatory markers were also dysregulated in OB, HT, raphe, and LC. Our results suggest that alcohol triggers a compensatory upregulation of ACE2 in the brain due to disturbed RAS and may increase the risk or severity of SARS-CoV-2 infection.

Normalization of HPA Axis, Cholinergic Neurotransmission, and Inhibiting Brain Oxidative and Inflammatory Dynamics Are Associated with The Adaptogenic-like Effect of Rutin Against Psychosocial Defeat Stress.

Social defeat stress (SDS) due to changes in biochemical functions has been implicated in the pathogenesis of affective and cognitive disorders. Employing pharmacological approach with adaptogens in the management and treatment of psychosocial stress is increasingly receiving scientific attention. In this study, we investigated the neuroprotective effect of rutin, a bioflavonoid with neuroprotective and anti-inflammatory functions on neurobehavioral and neuro-biochemical changes in mice exposed to SDS. Groups of mice named the intruder mice received normal saline(10 mL/kg), rutin (5, 10, and 20mg/kg, i.p.), and ginseng (50mg/kg, i.p.) daily for 14days, and then followed by 10min daily SDS (physical/psychological) exposures to aggressor micefrom days 7-14. Investigations consisting of neurobehavioral (locomotion, memory, anxiety, and depression)phenotypes, neuro-biochemical (oxidative, nitrergic, cholinergic, and pro-inflammatory cytokines) levelsin discrete brain regions, and hypothalamic-pituitary-adrenal(HPA) axis consistingadrenalweight, corticosterone, and glucoseconcentrations were assessed. Rutin restored the neurobehavioral deficits and reduced the activity of acetylcholinesterase in the brains. Adrenal hypertrophy, increased serum glucose and corticosterone levels were significantly attenuated by rutin. SDS-induced release of tumor necrosis factor-alpha and interleukin-6 in the striatum, prefrontal cortex, and hippocampus were also suppressed by rutin in a brain-region-dependent manner. Moreover, SDS-induced oxidative stress characterized by low antioxidants (glutathione, superoxide-dismutase, catalase) and lipid peroxidation and nitrergic stress were reversed by rutin in discrete brain regions. Collectively, our data suggest that rutin possesses an adoptogenic potential in mice exposed to SDS via normalization of HPA, oxidative/nitrergic, and neuroinflammatory inhibitions. Thus, may be adopted in the management of neuropsychiatric syndrome due to psychosocial stress.

Blood-cerebrospinal fluid barrier opening by modified single pulse transcranial focused shockwave

Transcranial focused shockwave (FSW) is a novel noninvasive brain stimulation that can open blood-brain barriers (BBB) and blood-cerebrospinal fluid barriers (BCSFB) with a single low-energy (energy flux density 0.03 mJ/mm2) pulse and low-dose microbubbles (2 × 106/kg). Similar to focused ultrasound, FSW deliver highly precise stimulation of discrete brain regions with adjustable focal lengths that essentially covers the whole brain. By opening the BCSFB, it allows for rapid widespread drug delivery to the whole brain by cerebrospinal fluid (CSF) circulation. Although no definite adverse effect or permeant injury was noted in our previous study, microscopic hemorrhage was infrequently observed. Safety concerns remain the major obstacle to further application of FSW in brain. To enhance its applicability, a modified single pulse FSW technique was established that present 100% opening rate but much less risk of adverse effect than previous methods. By moving the targeting area 2.5 mm more superficially on the left lateral ventricle as compared with the previous methods, the microscopic hemorrhage rate was reduced to zero. We systemically examine the safety profiles of the modified FSW-BCSFB opening regarding abnormal behavior and brain injury or hemorrhage 72 hr after 0, 1, and 10 pulses of FSW-treatment. Animal behavior, physiological monitor, and brain MRI were examined and recorded. Brain section histology was examined for hemorrhage, apoptosis, inflammation, oxidative stress related immunohistochemistry and biomarkers. The single pulse FSW group demonstrated no mortality or gross/microscopic hemorrhage (N = 30), and no observable changes in all examined outcomes, while 10 pulses of FSW was found to be associated with microscopic and temporary RBC extravasation (N = 6/30), and abnormal immunohistochemistry biomarkers which showed a trend of recovery at 72 hrs. The results suggest that single pulse low-energy FSW-BCSFB opening is effective, safe and poses minimal risk of injury to brain tissue (Sprague Dawley, SD rats).