Neurobiology of Disease最新文献

{"title":"Spectral and coupling characteristics of somatosensory cortex and centromedian thalamus differentiate between pre- and inter-ictal 5–9 Hz oscillations in a genetic rat model of absence epilepsy","authors":"Eleni Nikalexi ,&nbsp;Vladimir Maksimenko ,&nbsp;Thomas Seidenbecher ,&nbsp;Thomas Budde ,&nbsp;Hans-Christian Pape ,&nbsp;Annika Lüttjohann","doi":"10.1016/j.nbd.2024.106777","DOIUrl":"10.1016/j.nbd.2024.106777","url":null,"abstract":"<div><div>Spike-wave-discharges (SWD) are the electrophysiological hallmark of absence epilepsy. SWD are generated in the thalamo-cortical network and a seizure onset zone was identified in the somatosensory cortex (S1). We have shown before that inhibition of the centromedian thalamic nucleus (CM) in GAERS rats resulted in a selective suppression of the spike component while rhythmic cortical 5–9 Hz oscillations remained present. Such oscillations are often seen to precede SWD activity in this well-validated genetic rat model of absence epilepsy, but are also seen in seizure-free periods. The present study characterizes the profile of 5–9 Hz oscillations in thalamo-cortical circuits during pre- and inter-ictal states.</div><div>Here we recorded local-field-potentials in S1, CM and the secondary motor cortex of GAERS. Time-frequency analysis was used to assess spectral power and non-linear-association analysis was used to determine coupling strength and directionality between brain areas. Phase-specific electrical stimulation was used to compare cortical excitability and to assess the risk for epileptic afterdischarges.</div><div>Coupling strength and spectral power were higher for the inter-ictal compared to the pre-ictal 5–9 Hz oscillations. However, coupling strength during pre-ictal oscillations was higher than during passive wakefulness. Double pulse stimulation during 5–9 Hz oscillations was more likely to induce epileptic afterdischarges compared to stimulation during passive wakefulness. While no overall differences in cortical excitability were revealed, phase-specific differences in excitability were noticed during the oscillation.</div><div>Our findings indicate that intermediate coupling between S1 and CM favors SWD generation, thereby adding to the previous notion that 5–9 Hz oscillations represent high-risk periods for seizure generation. In general, pre-ictal oscillations display a unique electrophysiological profile in GAERS that might pave the way for qualification as biomarker for SWD generation and seizure prediction.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106777"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-synuclein pathology enhances peripheral and CNS immune responses to bacterial endotoxins","authors":"Anna-Sophia Hartke ,&nbsp;Cara S. Schreiber ,&nbsp;Kristina Lau ,&nbsp;Ivo Wiesweg ,&nbsp;Inken Waltl ,&nbsp;Ulrich Kalinke ,&nbsp;Franziska Richter ,&nbsp;Christopher Käufer","doi":"10.1016/j.nbd.2024.106773","DOIUrl":"10.1016/j.nbd.2024.106773","url":null,"abstract":"<div><div>Increasing evidence points to infectious diseases as contributor to the pathogenesis of neurodegeneration in Parkinson's disease (PD), probably driven by a peripheral and CNS inflammatory response together with alpha-synuclein (aSyn) pathology. Pro-inflammatory lipopolysaccharide (LPS) endotoxin is suggested as a risk factor, and LPS shedding gram-negative bacteria are more prevalent in the gut-microbiome of PD patients. Here, we investigated whether LPS could contribute to the neurodegenerative disease progression via neuroinflammation, especially under conditions of aSyn pathology. To investigate this, we created a double-hit model based on the Thy1-aSyn mouse line (line 61), an established aSyn-overexpression model of PD, exposed to a single intraperitoneal injection of LPS at a dose of 0.8 mg/kg (equivalent to approximately 1,200,000 EU/kg). Clinical parameters, flow cytometry of blood and immune cells in the brain, brain immunohistology and motor behavior were evaluated over time. As expected, the LPS dosage induced transient acute symptoms and mild weight loss in mice, with full recovery after 7 days. In aSyn over-expressing mice, this single low dose of LPS was sufficient to alter the expression of specific markers on blood and brain immune cells and induced brain region-specific microgliosis that were present at 7 days post LPS injection. At 14 days post injection of LPS, aSyn expression was reduced in wild-type mice, indicating a specific response of the endogenous protein to the endotoxin. At this early time point, motor behavior is not yet robustly impacted by the observed pathological alterations. In conclusion, aSyn pathology renders the peripheral and central immune response more sensitive to a single low dose of bacterial endotoxin, which mimics a transient dysbiosis or gut infection. Thus, this data suggests that such peripheral triggers should be monitored in PD patients for instance by blood immune cell response as biomarkers. Furthermore, results from this study lend further support to the development of treatments aiming to reduce the impact of bacterial dysbiosis as a promising strategy to mitigate PD progression.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106773"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice","authors":"Colette Reinhold ,&nbsp;Susanne Knorr ,&nbsp;Rhonda L. McFleder ,&nbsp;Lisa Harder-Rauschenberger ,&nbsp;Tom Gräfenhan ,&nbsp;Andreas Schlosser ,&nbsp;Michael Sendtner ,&nbsp;Jens Volkmann ,&nbsp;Chi Wang Ip","doi":"10.1016/j.nbd.2024.106783","DOIUrl":"10.1016/j.nbd.2024.106783","url":null,"abstract":"<div><div>DYT-THAP1 dystonia is a monogenetic form of dystonia, a movement disorder characterized by the involuntary co-contraction of agonistic and antagonistic muscles. The disease is caused by mutations in the <em>THAP1</em> gene, although the precise mechanisms by which these mutations contribute to the pathophysiology of dystonia remain unclear. The incomplete penetrance of DYT-THAP1 dystonia, estimated at 40 to 60 %, suggests that an environmental trigger may be required for the manifestation of the disease in genetically predisposed individuals. To investigate the gene-environment interaction in the development of dystonic features, we performed a sciatic nerve crush injury in a genetically predisposed DYT-THAP1 heterozygous knockout mouse model (Thap1^+/−). We employed a multi-omic assessment to study the pathophysiological pathways underlying the disease. Phenotypic analysis using an unbiased deep learning algorithm revealed that nerve-injured Thap1^+/− mice exhibited significantly more dystonia like movements (DLM) over the course of the 12-week experiment compared to naive Thap1^+/− mice. In contrast, nerve-injured wildtype (wt) mice only showed a significant increase in DLM compared to their naive counterpart during the first weeks after injury. Furthermore, at week 11 after nerve crush, nerve-injured Thap1^+/− mice displayed significantly more DLM than nerve-injured wt counterparts. Multi-omic analysis of the cerebellum, striatum and cortex in nerve-injured Thap1^+/− mice revealed differences that are indicative of an altered energy metabolism compared to naive Thap1^+/− and nerve-injured wt animals. These findings suggest that aberrant energy metabolism in brain regions relevant to dystonia may underlie the dystonic phenotype observed in nerve injured Thap1^+/− mice.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106783"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy","authors":"Miaomiao Mao ,&nbsp;Nikola Jancovski ,&nbsp;Yafit Kushner ,&nbsp;Lucas Teasdale ,&nbsp;Phan Truong ,&nbsp;Kun Zhou ,&nbsp;Samuel Reid ,&nbsp;Linghan Jia ,&nbsp;Ye Htet Aung ,&nbsp;Melody Li ,&nbsp;Christopher A. Reid ,&nbsp;Sean Byars ,&nbsp;Ingrid Scheffer ,&nbsp;Steven Petrou ,&nbsp;Snezana Maljevic","doi":"10.1016/j.nbd.2024.106782","DOIUrl":"10.1016/j.nbd.2024.106782","url":null,"abstract":"<div><h3>Background</h3><div>Developmental and epileptic encephalopathies (DEE) are rare but severe neurodevelopmental disorders characterised by early-onset seizures often combined with developmental delay, behavioural and cognitive deficits. Treatment for DEEs is currently limited to seizure control and provides no benefits to the patients' developmental and cognitive outcomes. Genetic variants are the most common cause of DEE with <em>KCNQ2</em> being one of the most frequently identified disease-causing genes. <em>KCNQ2</em> encodes a voltage-gated potassium channel K_V7.2 widely expressed in the central nervous system and critically involved in the regulation of neuronal excitability. In this study, we aimed to characterise a <em>KCNQ2</em> variant (K556E) found in a female patient with DEE using a heterologous expression system and a knock-in mouse model.</div></div><div><h3>Methods</h3><div>Wild-type <em>KCNQ2</em> or K556E variant were expressed in Chinese Hamster Ovary (CHO) cells (with or without <em>KCNQ3</em>) and their biophysical properties assessed using patch clamp recordings. We further engineered a new <em>Kcnq2</em> DEE mouse model (K557E) based on the K556E variant and characterised it using behavioural, electrophysiological, and transcriptome analysis.</div></div><div><h3>Results</h3><div>A mild loss of function was observed only when the mutant channel was co-expressed with <em>KCNQ3</em> in the heterologous system. The heterozygous knock-in mice showed a reduced survival rate and increased susceptibility to induced seizures. Electrophysiology recordings in brain slices revealed a hyperexcitable phenotype for cortical layer 2/3 pyramidal neurons with retigabine (K_V7 channel opener) able to rescue both the increased sensitivity to chemically-induced seizures in vivo and neuronal excitability ex vivo. Whole-brain RNA sequencing revealed numerous differentially expressed genes and biological pathways pointing at dysregulation of early developmental processes.</div></div><div><h3>Conclusions</h3><div>Our study reports on a novel <em>Kcnq2</em> DEE mouse model recapitulating aspects of the disease phenotype with the electrophysiological and transcriptome analysis providing insights into <em>KCNQ2</em> DEE mechanisms that can be leveraged for future therapy development.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106782"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anxiety-like behavior and altered hippocampal activity in a transgenic mouse model of Fabry disease","authors":"Kai Kummer ,&nbsp;Jeiny Luna Choconta ,&nbsp;Marie-Luise Edenhofer ,&nbsp;Archana Bajpai ,&nbsp;Gopuraja Dharmalingam ,&nbsp;Theodora Kalpachidou ,&nbsp;David A. Collier ,&nbsp;Michaela Kress","doi":"10.1016/j.nbd.2025.106797","DOIUrl":"10.1016/j.nbd.2025.106797","url":null,"abstract":"<div><h3>Background</h3><div>Fabry disease (FD) patients are known to be at high risk of developing neuropsychiatric symptoms such as anxiety, depression and cognitive deficits. Despite this, they are underdiagnosed and inadequately treated. It is unknown whether these symptoms arise from pathological glycosphingolipid deposits or from cerebrovascular abnormalities affecting neuronal functions in the central nervous system. We therefore aimed to fill this knowledge gap by exploring a transgenic FD mouse model with a combination of behavior, transcriptomic, functional and morphological assessments, with a particular focus on the hippocampus.</div></div><div><h3>Results</h3><div>Male FD mice exhibited increased anxiety-like behavior in the open field test, accompanied by a reduced exploratory drive in the Barnes maze, which could be related to the increased deposition of globotriaosylceramide (Gb3) identified in the dentate gyrus (DG). Hippocampus single-cell sequencing further revealed that Gb3 accumulation was associated with differential gene expression in neuronal and non-neuronal cell populations with granule, excitatory and interneurons, as well as microglia and endothelial cells as the main clusters with the most dysregulated genes. Particularly FD hippocampal neurons showed decreased electrical baseline activity in the DG and increased activity in the CA3 region of acutely dissected hippocampal slices.</div></div><div><h3>Conclusions</h3><div>Our study highlights transcriptional and functional alterations in non-neuronal and neuronal cell clusters in the hippocampus of FD mice, which are suggested to be causally related to anxiety-like behavior developing as a consequence of FD pathology in mouse models of the disease and in patients.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106797"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors","authors":"Brianne Dentel ,&nbsp;Lidiette Angeles-Perez ,&nbsp;Abigail Y. Flores ,&nbsp;Katherine Lei ,&nbsp;Chongyu Ren ,&nbsp;Andrea Pineda Sanchez ,&nbsp;Peter T. Tsai","doi":"10.1016/j.nbd.2025.106790","DOIUrl":"10.1016/j.nbd.2025.106790","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Loss of function in the subunits of the GTPase-activating protein (GAP) activity toward Rags-1 (GATOR1) complex, an amino-acid sensitive negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), is implicated in both genetic familial epilepsies and Neurodevelopmental Disorders (NDDs) (&lt;span&gt;&lt;span&gt;Baldassari et al., 2018&lt;/span&gt;&lt;/span&gt;). Previous studies have found seizure phenotypes and increased activity resulting from conditional deletion of GATOR1 function from forebrain excitatory neurons (&lt;span&gt;&lt;span&gt;Yuskaitis et al., 2018&lt;/span&gt;&lt;/span&gt;; &lt;span&gt;&lt;span&gt;Dentel et al., 2022&lt;/span&gt;&lt;/span&gt;); however, studies focused on understanding mechanisms contributing to NDD-relevant behaviors are lacking, especially studies understanding the contributions of GATOR1's critical GAP catalytic subunit, nitrogen permease regulator like-2 (&lt;em&gt;Nprl2)&lt;/em&gt;. Given the clinical phenotypes observed in patients with &lt;em&gt;Nprl2&lt;/em&gt; mutations, in this study, we sought to investigate the neuronal cell type contributions of &lt;em&gt;Nprl2&lt;/em&gt; to NDD behaviors. We conditionally deleted &lt;em&gt;Nprl2&lt;/em&gt; broadly in most neurons (&lt;em&gt;Synapsin1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;cre&lt;/em&gt;&lt;/sup&gt;), in inhibitory neurons only (&lt;em&gt;Vgat&lt;/em&gt;&lt;sup&gt;&lt;em&gt;cre&lt;/em&gt;&lt;/sup&gt;), and in Purkinje cells within the cerebellum (&lt;em&gt;L7&lt;/em&gt;&lt;sup&gt;&lt;em&gt;cre&lt;/em&gt;&lt;/sup&gt;). Broad neuronal deletion of &lt;em&gt;Nprl2&lt;/em&gt; resulted in seizures, social and learning deficits, and hyperactivity. In contrast, deleting &lt;em&gt;Nprl2&lt;/em&gt; from inhibitory neurons led to increased motor learning, hyperactive behavior, in addition to social and learning deficits. Lastly, Purkinje cell (PC) loss of &lt;em&gt;Nprl2&lt;/em&gt; also led to learning and social deficits but did not affect locomotor activity. These phenotypes enhance understanding of the spectrum of disease found in human populations with GATOR1 loss of function and highlight the significance of distinct cellular populations to NDD-related behaviors.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Significance statement&lt;/h3&gt;&lt;div&gt;We aim to elucidate the neuronal-specific contributions of nitrogen permease regulator like-2 (&lt;em&gt;Nprl2)&lt;/em&gt; to its neurodevelopmental disorder (NDD)-relevant phenotypes. We conditionally deleted &lt;em&gt;Nprl2&lt;/em&gt; broadly in neurons (&lt;em&gt;Syn1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;cre&lt;/em&gt;&lt;/sup&gt;), in inhibitory neurons (&lt;em&gt;Vgat&lt;/em&gt;&lt;sup&gt;&lt;em&gt;cre&lt;/em&gt;&lt;/sup&gt;), and in cerebellar Purkinje cells (&lt;em&gt;L7&lt;/em&gt;&lt;sup&gt;&lt;em&gt;cre&lt;/em&gt;&lt;/sup&gt;). We identify seizures only in the &lt;em&gt;Syn1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;cre&lt;/em&gt;&lt;/sup&gt; conditional mutant (cKO); hyperactivity, learning difficulties, social deficits, and impulsivity in the &lt;em&gt;Syn1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;cre&lt;/em&gt;&lt;/sup&gt; and &lt;em&gt;Vgat&lt;/em&gt;&lt;sup&gt;&lt;em&gt;cre&lt;/em&gt;&lt;/sup&gt; cKOs; and social deficits, and fear learning deficits in &lt;em&gt;L7&lt;/em&gt;&lt;sup&gt;&lt;em&gt;cre&lt;/em&gt;&lt;/sup&gt; cKOs. To our knowledge, we are the first to describe the behavioral contributions of &lt;em&gt;Nprl2&lt;/em&gt;'s function across multiple cell types. Our findings highlight both critical roles for &lt;em&gt;Nprl2&lt;/em&gt; in learning and behavior and also distinct contrib","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106790"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Positron emission tomography molecular imaging for pathological visualization in multiple system atrophy","authors":"La Dong ,&nbsp;Rui Zhou ,&nbsp;Jinyun Zhou ,&nbsp;Ke Liu ,&nbsp;Chentao Jin ,&nbsp;Jing Wang ,&nbsp;Chenxi Xue ,&nbsp;Mei Tian ,&nbsp;Hong Zhang ,&nbsp;Yan Zhong","doi":"10.1016/j.nbd.2025.106828","DOIUrl":"10.1016/j.nbd.2025.106828","url":null,"abstract":"<div><div>Multiple system atrophy (MSA) is a complex, heterogeneous neurodegenerative disorder characterized by a multifaceted pathogenesis. Its key pathological hallmark is the abnormal aggregation of α-synuclein, which triggers neuroinflammation, disrupts both dopaminergic and non-dopaminergic systems, and results in metabolic abnormalities in the brain. Positron emission tomography (PET) is a non-invasive technique that enables the visualization, characterization, and quantification of these pathological processes from diverse perspectives using radiolabeled agents. PET imaging of molecular events provides valuable insights into the underlying pathomechanisms of MSA and holds significant promise for the development of imaging biomarkers, which could greatly improve disease assessment and management. In this review, we focused on the pathological mechanisms of MSA, summarized relevant targets and radiopharmaceuticals, and discussed the clinical applications and future perspectives of PET molecular imaging in MSA.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106828"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New perspectives on the glymphatic system and the relationship between glymphatic system and neurodegenerative diseases","authors":"Yan-rui Sun ,&nbsp;Qian-Kun Lv ,&nbsp;Jun-Yi Liu ,&nbsp;Fen Wang ,&nbsp;Chun-Feng Liu","doi":"10.1016/j.nbd.2025.106791","DOIUrl":"10.1016/j.nbd.2025.106791","url":null,"abstract":"<div><div>Neurodegenerative diseases (ND) are characterized by the accumulation of aggregated proteins. The glymphatic system, through its rapid exchange mechanisms between cerebrospinal fluid (CSF) and interstitial fluid (ISF), facilitates the movement of metabolic substances within the brain, serving functions akin to those of the peripheral lymphatic system. This emerging waste clearance mechanism offers a novel perspective on the removal of pathological substances in ND. This article elucidates recent discoveries regarding the glymphatic system and updates relevant concepts within its model. It discusses the potential roles of the glymphatic system in ND, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple system atrophy (MSA), and proposes the glymphatic system as a novel therapeutic target for these conditions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106791"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nrf2 phosphorylation contributes to acquisition of pericyte reprogramming via the PKCδ pathway","authors":"Rika Sakuma,&nbsp;Yusuke Minato,&nbsp;Seishi Maeda,&nbsp;Hideshi Yagi","doi":"10.1016/j.nbd.2025.106824","DOIUrl":"10.1016/j.nbd.2025.106824","url":null,"abstract":"<div><div>Pericytes (PCs) are vascular mural cells embedded in the basement membrane of micro blood vessels. It has been proposed using a C.B-17 mouse model of stroke that normal brain PCs are converted to ischemic PCs (iPCs), some of which express various stem cell markers. We previously reported that nuclear factor erythroid-2-related factor 2 (Nrf2) protected against oxidative stress following ischemia and promoted the PC reprogramming process. The present study examined the molecular mechanisms underlying the induction of Nrf2. We revealed that oxidative stress and pNrf2 induced by stroke proceeded the expression of nestin in meningeal cells and reactive PCs within the post-stroke area. PKCδ inhibitor treatment suppressed pNrf2 activation and restored the down-regulated expression of stem cell markers in iPCs <em>in vitro</em>. The PKCδ inhibitor treatment also suppressed the production of iPCs. These results suggest the potential of Nrf2 phosphorylation via PKCδ as a novel strategy for the treatment of ischemic injury.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106824"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic cannabis use differentially modulates neural oscillations serving the manipulate versus maintain components of working memory processing","authors":"Peihan J. Huang ,&nbsp;Jake J. Son ,&nbsp;Yasra Arif ,&nbsp;Jason A. John ,&nbsp;Lucy K. Horne ,&nbsp;Mikki Schantell ,&nbsp;Seth D. Springer ,&nbsp;Maggie P. Rempe ,&nbsp;Hannah J. Okelberry ,&nbsp;Abraham D. Killanin ,&nbsp;Ryan Glesinger ,&nbsp;Anna T. Coutant ,&nbsp;Thomas W. Ward ,&nbsp;Madelyn P. Willett ,&nbsp;Hallie J. Johnson ,&nbsp;Elizabeth Heinrichs-Graham ,&nbsp;Tony W. Wilson","doi":"10.1016/j.nbd.2025.106792","DOIUrl":"10.1016/j.nbd.2025.106792","url":null,"abstract":"<div><div>The legalization of recreational cannabis use has expanded the availability of this psychoactive substance in the United States. Research has shown that chronic cannabis use is associated with altered working memory function, however, the brain areas and neural dynamics underlying these affects remain poorly understood. In this study, we leveraged magnetoencephalography (MEG) to investigate neurophysiological activity in 45 participants (22 heavy cannabis users) during a numerical WM task, whereby participants were asked to either maintain or manipulate (i.e., rearrange in ascending order) a group of visually presented numbers. Significant oscillatory responses were imaged using a beamformer and subjected to whole-brain ANOVAs. Notably, we found that cannabis users exhibited significantly weaker alpha oscillations in superior parietal, occipital, and other regions during the encoding phase relative to nonusers. Interestingly, during the maintenance phase, there was a group-by-condition interaction in the right inferior frontal gyrus, left prefrontal, parietal, and other regions, such that cannabis users exhibited weaker alpha and beta oscillations relative to nonusers during maintain trials. Additionally, chronic cannabis users exhibited stronger alpha and beta maintenance responses in these same brain regions and prolonged reaction times during manipulate relative to maintain trials, while no such differences were found in nonusers. Neurobehavioral relationships were also detected in the prefrontal cortices of nonusers, but not cannabis users. In sum, chronic cannabis users exhibit weaker neural oscillations during working memory encoding but may compensate for these deficiencies through stronger oscillatory responses during memory maintenance, especially during strenuous tasks such as manipulating the to-be remembered items.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106792"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}