29,629 results on '"Neurology & Neurosurgery"'
Search Results
2. Calcium plays an essential role in early-stage dendrite injury detection and regeneration
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Duarte, Vinicius N, Lam, Vicky T, Rimicci, Dario S, and Thompson-Peer, Katherine L
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Biomedical and Clinical Sciences ,Neurosciences ,Physical Injury - Accidents and Adverse Effects ,Traumatic Head and Spine Injury ,Regenerative Medicine ,1.1 Normal biological development and functioning ,Neurological ,Dendrites ,Animals ,Calcium ,Nerve Regeneration ,Humans ,Mice ,Potassium Channels ,Inwardly Rectifying ,Mice ,Transgenic ,Dendrite injury ,Dendrite repair ,Dendrite regeneration ,Drosophila ,Injury detection ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Dendrites are injured in a variety of clinical conditions such as traumatic brain and spinal cord injuries and stroke. How neurons detect injury directly to their dendrites to initiate a pro-regenerative response has not yet been thoroughly investigated. Calcium plays a critical role in the early stages of axonal injury detection and is also indispensable for regeneration of the severed axon. Here, we report cell and neurite type-specific differences in laser injury-induced elevations of intracellular calcium levels. Using a human KCNJ2 transgene, we demonstrate that hyperpolarizing neurons only at the time of injury dampens dendrite regeneration, suggesting that inhibition of injury-induced membrane depolarization (and thus early calcium influx) plays a role in detecting and responding to dendrite injury. In exploring potential downstream calcium-regulated effectors, we identify L-type voltage-gated calcium channels, inositol triphosphate signaling, and protein kinase D activity as drivers of dendrite regeneration. In conclusion, we demonstrate that dendrite injury-induced calcium elevations play a key role in the regenerative response of dendrites and begin to delineate the molecular mechanisms governing dendrite repair.
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- 2024
3. Triggering Receptor Expressed on Myeloid Cells 2 Alleviated Sevoflurane-Induced Developmental Neurotoxicity via Microglial Pruning of Dendritic Spines in the CA1 Region of the Hippocampus
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Deng, Li, Song, Shao-Yong, Zhao, Wei-Ming, Meng, Xiao-Wen, Liu, Hong, Zheng, Qing, Peng, Ke, and Ji, Fu-Hai
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Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Pediatric ,Behavioral and Social Science ,Neurological ,CA1 neurons ,Dendritic spines ,Developmental neurotoxicity ,Microglia ,Sevoflurane ,TREM2 ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Sevoflurane induces developmental neurotoxicity in mice; however, the underlying mechanisms remain unclear. Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for microglia-mediated synaptic refinement during the early stages of brain development. We explored the effects of TREM2 on dendritic spine pruning during sevoflurane-induced developmental neurotoxicity in mice. Mice were anaesthetized with sevoflurane on postnatal days 6, 8, and 10. Behavioral performance was assessed using the open field test and Morris water maze test. Genetic knockdown of TREM2 and overexpression of TREM2 by stereotaxic injection were used for mechanistic experiments. Western blotting, immunofluorescence, electron microscopy, three-dimensional reconstruction, Golgi staining, and whole-cell patch-clamp recordings were performed. Sevoflurane exposures upregulated the protein expression of TREM2, increased microglia-mediated pruning of dendritic spines, and reduced synaptic multiplicity and excitability of CA1 neurons. TREM2 genetic knockdown significantly decreased dendritic spine pruning, and partially aggravated neuronal morphological abnormalities and cognitive impairments in sevoflurane-treated mice. In contrast, TREM2 overexpression enhanced microglia-mediated pruning of dendritic spines and rescued neuronal morphological abnormalities and cognitive dysfunction. TREM2 exerts a protective role against neurocognitive impairments in mice after neonatal exposures to sevoflurane by enhancing microglia-mediated pruning of dendritic spines in CA1 neurons. This provides a potential therapeutic target in the prevention of sevoflurane-induced developmental neurotoxicity.
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- 2024
4. Organelle phenotyping and multi‐dimensional microscopy identify C1q as a novel regulator of microglial function
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Sakthivel, Pooja S, Scipioni, Lorenzo, Karam, Josh, Keulen, Zahara, Blurton‐Jones, Mathew, Gratton, Enrico, and Anderson, Aileen J
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Biochemistry and Cell Biology ,Biological Sciences ,Stem Cell Research - Induced Pluripotent Stem Cell ,Genetics ,Stem Cell Research ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,C1q ,complement ,inflammation ,microglia ,organelles ,Neurosciences ,Neurology & Neurosurgery ,Biochemistry and cell biology - Abstract
Microglia, the immune cells of the central nervous system, are dynamic and heterogenous cells. While single cell RNA sequencing has become the conventional methodology for evaluating microglial state, transcriptomics do not provide insight into functional changes, identifying a critical gap in the field. Here, we propose a novel organelle phenotyping approach in which we treat live human induced pluripotent stem cell-derived microglia (iMGL) with organelle dyes staining mitochondria, lipids, lysosomes and acquire data by live-cell spectral microscopy. Dimensionality reduction techniques and unbiased cluster identification allow for recognition of microglial subpopulations with single-cell resolution based on organelle function. We validated this methodology using lipopolysaccharide and IL-10 treatment to polarize iMGL to an "inflammatory" and "anti-inflammatory" state, respectively, and then applied it to identify a novel regulator of iMGL function, complement protein C1q. While C1q is traditionally known as the initiator of the complement cascade, here we use organelle phenotyping to identify a role for C1q in regulating iMGL polarization via fatty acid storage and mitochondria membrane potential. Follow up evaluation of microglia using traditional read outs of activation state confirm that C1q drives an increase in microglia pro-inflammatory gene production and migration, while suppressing microglial proliferation. These data together validate the use of a novel organelle phenotyping approach and enable better mechanistic investigation of molecular regulators of microglial state.
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- 2024
5. The identification of intact HIV proviral DNA from human cerebrospinal fluid
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Zhang, Zhan, Reece, Monica D, Roa, Sebastian, Tyor, William, Franklin, Donald R, Letendre, Scott L, Marconi, Vincent C, Anderson, Albert M, and Gavegnano, Christina
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Mental Health ,HIV/AIDS ,Neurosciences ,Infectious Diseases ,Clinical Research ,Sexually Transmitted Infections ,Infection ,Central nervous system ,Cerebrospinal fluid ,HIV ,Inflammation ,Reservoir ,Pharmacology and Pharmaceutical Sciences ,Public Health and Health Services ,Neurology & Neurosurgery ,Pharmacology and pharmaceutical sciences ,Biological psychology - Abstract
We evaluated the HIV-1 DNA reservoir in peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) in people with HIV (PWH) and associations to cognitive dysfunction. Using the intact proviral DNA assay (IPDA), an emerging technique to identify provirus that may be the source of viral rebound, we assessed HIV DNA in CSF and PBMC in PWH regardless of antiretroviral therapy (ART). CSF was used as a sampling surrogate for the central nervous system (CNS) as opposed to tissue. IDPA results (3' defective, 5' defective, and intact HIV DNA) were analyzed by compartment (Wilcoxon signed rank; matched and unmatched pairs). Cognitive performance, measured via a battery of nine neuropsychological (NP) tests, were analyzed for correlation to HIV DNA (Spearman's rho). 11 CSF and 8 PBMC samples from PWH were evaluated both unmatched and matched. Total CSF HIV DNA was detectable in all participants and was significantly higher than in matched PBMCs (p = 0.0039). Intact CSF HIV DNA was detected in 7/11 participants and correlated closely with those in PBMCs but tended to be higher in CSF than in PBMC. CSF HIV DNA did not correlate with global NP performance, but higher values did correlate with worse executive function (p = 0.0440). Intact HIV DNA is frequently present in the CSF of PWH regardless of ART. This further supports the presence of an HIV CNS reservoir and provides a method to study CNS reservoirs during HIV cure studies. Larger studies are needed to evaluate relationships with CNS clinical outcomes.
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- 2024
6. Integration of photoperiodic and temperature cues by the circadian clock to regulate insect seasonal adaptations
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Hidalgo, Sergio and Chiu, Joanna C
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Biological Sciences ,Genetics ,Sleep Research ,Biotechnology ,1.1 Normal biological development and functioning ,Underpinning research ,Animals ,Photoperiod ,Seasons ,Circadian Clocks ,Adaptation ,Physiological ,Temperature ,Drosophila melanogaster ,Cues ,Insecta ,Circadian Rhythm ,Seasonal adaptations ,Circadian clock ,Splicing ,Neuropeptide ,Medical and Health Sciences ,Neurology & Neurosurgery ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Organisms adapt to unfavorable seasonal conditions to survive. These seasonal adaptations rely on the correct interpretation of environmental cues such as photoperiod, and temperature. Genetic studies in several organisms, including the genetic powerhouse Drosophila melanogaster, indicate that circadian clock components, such as period and timeless, are involved in photoperiodic-dependent seasonal adaptations, but our understanding of this process is far from complete. In particular, the role of temperature as a key factor to complement photoperiodic response is not well understood. The development of new sequencing technologies has proven extremely useful in understanding the plastic changes that the clock and other cellular components undergo in different environmental conditions, including changes in gene expression and alternative splicing. This article discusses the integration of photoperiod and temperature for seasonal biology as well as downstream molecular and cellular pathways involved in the regulation of physiological adaptations that occur with changing seasons. We focus our discussion on the current understanding of the involvement of the molecular clock and the circadian clock neuronal circuits in these adaptations in D. melanogaster.
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- 2024
7. Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size
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Lin, Lin, Zhao, Jingrong, Kubota, Naoto, Li, Zhelin, Lam, Yi-Li, Nguyen, Lauren P, Yang, Lu, Pokharel, Sheela P, Blue, Steven M, Yee, Brian A, Chen, Renee, Yeo, Gene W, Chen, Chun-Wei, Chen, Liang, and Zheng, Sika
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Biomedical and Clinical Sciences ,Neurosciences ,Brain Disorders ,Stem Cell Research - Nonembryonic - Non-Human ,Stem Cell Research ,Rare Diseases ,Pediatric ,Stem Cell Research - Embryonic - Non-Human ,Congenital Structural Anomalies ,Genetics ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Tumor Suppressor Protein p53 ,Mice ,Brain ,Mice ,Knockout ,Neural Stem Cells ,Nonsense Mediated mRNA Decay ,Epistasis ,Genetic ,Microcephaly ,Cell Cycle ,Cyclin-Dependent Kinase Inhibitor p21 ,RNA-Binding Proteins ,EJC ,PAX6 ,TBR2 ,Upf1 ,Upf3a ,Upf3b ,cell division ,neurogenesis ,p21 ,p53 ,progenitor cell competence ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Mutations in human nonsense-mediated mRNA decay (NMD) factors are enriched in neurodevelopmental disorders. We show that deletion of key NMD factor Upf2 in mouse embryonic neural progenitor cells causes perinatal microcephaly but deletion in immature neurons does not, indicating NMD's critical roles in progenitors. Upf2 knockout (KO) prolongs the cell cycle of radial glia progenitor cells, promotes their transition into intermediate progenitors, and leads to reduced upper-layer neurons. CRISPRi screening identified Trp53 knockdown rescuing Upf2KO progenitors without globally reversing NMD inhibition, implying marginal contributions of most NMD targets to the cell cycle defect. Integrated functional genomics shows that NMD degrades selective TRP53 downstream targets, including Cdkn1a, which, without NMD suppression, slow the cell cycle. Trp53KO restores the progenitor cell pool and rescues the microcephaly of Upf2KO mice. Therefore, one physiological role of NMD in the developing brain is to degrade selective TRP53 targets to control progenitor cell cycle and brain size.
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- 2024
8. Prenatal exposure to social adversity and infant cortisol in the first year of life
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Keeton, Victoria F, Hoffmann, Thomas J, Goodwin, Kalisha Moneé, Powell, Bree, Tupuola, Sophia, and Weiss, Sandra J
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Reproductive Medicine ,Biomedical and Clinical Sciences ,Pediatric ,Behavioral and Social Science ,Mental Health ,Conditions Affecting the Embryonic and Fetal Periods ,Perinatal Period - Conditions Originating in Perinatal Period ,Mind and Body ,Violence Research ,Pediatric Research Initiative ,Clinical Research ,2.3 Psychological ,social and economic factors ,Aetiology ,Reproductive health and childbirth ,Good Health and Well Being ,Infant ,Infant ,Newborn ,Pregnancy ,Humans ,Female ,Child ,Hydrocortisone ,Longitudinal Studies ,Prenatal Exposure Delayed Effects ,Hypothalamo-Hypophyseal System ,Social Alienation ,Stress ,Psychological ,Pituitary-Adrenal System ,Saliva ,Social adversity ,infant cortisol ,prenatal stress ,fetal programming ,economic hardship ,biomarkers ,Clinical Sciences ,Neurology & Neurosurgery ,Clinical sciences ,Neurosciences - Abstract
Exposure to social adversity has been associated with cortisol dysregulation during pregnancy and in later childhood; less is known about how prenatal exposure to social stressors affects postnatal cortisol of infants. In a secondary analysis of data from a longitudinal study, we tested whether a pregnant woman's reports of social adversity during the third trimester were associated with their infant's resting cortisol at 1, 6, and 12 months postnatal. Our hypothesis was that prenatal exposure to social adversity would be associated with elevation of infants' cortisol. Measures included prenatal survey reports of social stressors and economic hardship, and resting cortisol levels determined from infant saliva samples acquired at each postnatal timepoint. Data were analyzed using linear mixed effects models. The final sample included 189 women and their infants (46.56% assigned female sex at birth). Prenatal economic hardship was significantly associated with infant cortisol at 6 months postnatal; reports of social stressors were not significantly associated with cortisol at any time point. Factors associated with hardship, such as psychological distress or nutritional deficiencies, may alter fetal HPA axis development, resulting in elevated infant cortisol levels. Developmental changes unique to 6 months of age may explain effects at this timepoint. More work is needed to better comprehend the complex pre- and post-natal physiologic and behavioral factors that affect infant HPA axis development and function, and the modifying role of environmental exposures.
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- 2024
9. The Ethical Landscape of Prodromal Parkinson Disease: Considerations for Shared Decision-Making and Health Equity.
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Hoy, Colin W and Chiong, Winston
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Parkinson's Disease ,Neurodegenerative ,Brain Disorders ,Aging ,Good Health and Well Being ,Humans ,Parkinson Disease ,Health Equity ,Prodromal Symptoms ,Decision Making ,Shared ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Published
- 2024
10. From bile acids to melancholia
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Klein, AS and Kheirbek, MA
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Neurosciences ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
In this issue of Neuron, Li, Zhang, et al.1 find that the bile acid receptor TGR5 in the lateral hypothalamus influences neuronal dynamics underlying stress-induced depression-like behaviors. Inhibition of these neurons produces antidepressant-like effects through a circuit that includes hippocampal CA3 and dorsolateral septum, revealing a novel potential therapeutic for depression.
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- 2024
11. Optimization-derived blood input function using a kernel method and its evaluation with total-body PET for brain parametric imaging
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Zhu, Yansong, Tran, Quyen, Wang, Yiran, Badawi, Ramsey D, Cherry, Simon R, Qi, Jinyi, Abbaszadeh, Shiva, and Wang, Guobao
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Biomedical and Clinical Sciences ,Health Sciences ,Clinical Research ,Biomedical Imaging ,Brain Disorders ,Bioengineering ,Humans ,Positron-Emission Tomography ,Brain ,Whole Body Imaging ,Image Processing ,Computer-Assisted ,Algorithms ,Tracer kinetic modeling ,Input function estimation ,Kernel method ,Total-body PET ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences - Abstract
Dynamic PET allows quantification of physiological parameters through tracer kinetic modeling. For dynamic imaging of brain or head and neck cancer on conventional PET scanners with a short axial field of view, the image-derived input function (ID-IF) from intracranial blood vessels such as the carotid artery (CA) suffers from severe partial volume effects. Alternatively, optimization-derived input function (OD-IF) by the simultaneous estimation (SIME) method does not rely on an ID-IF but derives the input function directly from the data. However, the optimization problem is often highly ill-posed. We proposed a new method that combines the ideas of OD-IF and ID-IF together through a kernel framework. While evaluation of such a method is challenging in human subjects, we used the uEXPLORER total-body PET system that covers major blood pools to provide a reference for validation.MethodsThe conventional SIME approach estimates an input function using a joint estimation together with kinetic parameters by fitting time activity curves from multiple regions of interests (ROIs). The input function is commonly parameterized with a highly nonlinear model which is difficult to estimate. The proposed kernel SIME method exploits the CA ID-IF as a priori information via a kernel representation to stabilize the SIME approach. The unknown parameters are linear and thus easier to estimate. The proposed method was evaluated using 18F-fluorodeoxyglucose studies with both computer simulations and 20 human-subject scans acquired on the uEXPLORER scanner. The effect of the number of ROIs on kernel SIME was also explored.ResultsThe estimated OD-IF by kernel SIME showed a good match with the reference input function and provided more accurate estimation of kinetic parameters for both simulation and human-subject data. The kernel SIME led to the highest correlation coefficient (R = 0.97) and the lowest mean absolute error (MAE = 10.5 %) compared to using the CA ID-IF (R = 0.86, MAE = 108.2 %) and conventional SIME (R = 0.57, MAE = 78.7 %) in the human-subject evaluation. Adding more ROIs improved the overall performance of the kernel SIME method.ConclusionThe proposed kernel SIME method shows promise to provide an accurate estimation of the blood input function and kinetic parameters for brain PET parametric imaging.
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- 2024
12. Cell-type-specific effects of age and sex on human cortical neurons
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Chien, Jo-Fan, Liu, Hanqing, Wang, Bang-An, Luo, Chongyuan, Bartlett, Anna, Castanon, Rosa, Johnson, Nicholas D, Nery, Joseph R, Osteen, Julia, Li, Junhao, Altshul, Jordan, Kenworthy, Mia, Valadon, Cynthia, Liem, Michelle, Claffey, Naomi, O'Connor, Caz, Seeker, Luise A, Ecker, Joseph R, Behrens, M Margarita, and Mukamel, Eran A
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Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Genetics ,Women's Health ,Human Genome ,Aging ,1.1 Normal biological development and functioning ,Underpinning research ,Neurological ,DNA methylation ,EGR1 ,X inactivation ,aging ,epigenome ,frontal cortex ,sex differences ,single cell ,telomere ,transcriptome ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes with advanced age. Using single-nucleus multi-omic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex from young adult and aged donors, we found widespread age- and sex-related variation in specific neuron types. The proportion of inhibitory SST- and VIP-expressing neurons was reduced in aged donors. Excitatory neurons had more profound age-related changes in their gene expression and DNA methylation than inhibitory cells. Hundreds of genes involved in synaptic activity, including EGR1, were less expressed in aged adults. Genes located in subtelomeric regions increased their expression with age and correlated with reduced telomere length. We further mapped cell-type-specific sex differences in gene expression and X-inactivation escape genes. Multi-omic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.
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- 2024
13. Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer’s Coordinating Center database
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Woodworth, Davis C, Nguyen, Katelynn M, Sordo, Lorena, Scambray, Kiana A, Head, Elizabeth, Kawas, Claudia H, Corrada, María M, Nelson, Peter T, and Sajjadi, S Ahmad
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Biomedical and Clinical Sciences ,Neurosciences ,Dementia ,Brain Disorders ,Alzheimer's Disease Related Dementias (ADRD) ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease ,Rare Diseases ,Aging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,Neurodegenerative ,ALS ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Humans ,Female ,Aged ,Male ,Alzheimer Disease ,DNA-Binding Proteins ,TDP-43 Proteinopathies ,Aged ,80 and over ,Databases ,Factual ,Frontotemporal Lobar Degeneration ,Brain ,Amyotrophic Lateral Sclerosis ,Hippocampus ,Middle Aged ,TDP-43 ,Limbic predominant age-related TDP-43 encephalopathy neuropathologic change ,Frontotemporal lobar degeneration ,Amyotrophic lateral sclerosis ,Hippocampal sclerosis of aging ,Alzheimer's disease ,National Alzheimer's coordinating center ,Alzheimer’s disease ,National Alzheimer’s coordinating center ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer's Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies ("Other TDP-43"). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer's disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.
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- 2024
14. Assessing the effectiveness of spatial PCA on SVM-based decoding of EEG data
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Zhang, Guanghui, Carrasco, Carlos D, Winsler, Kurt, Bahle, Brett, Cong, Fengyu, and Luck, Steven J
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Biomedical and Clinical Sciences ,Health Sciences ,Humans ,Electroencephalography ,Support Vector Machine ,Principal Component Analysis ,Female ,Male ,Adult ,Young Adult ,Evoked Potentials ,Brain ,Signal Processing ,Computer-Assisted ,EEG ,MVPA ,Group-based PCA ,Subject-based PCA ,Dimensionality reduction ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences - Abstract
Principal component analysis (PCA) has been widely employed for dimensionality reduction prior to multivariate pattern classification (decoding) in EEG research. The goal of the present study was to provide an evaluation of the effectiveness of PCA on decoding accuracy (using support vector machines) across a broad range of experimental paradigms. We evaluated several different PCA variations, including group-based and subject-based component decomposition and the application of Varimax rotation or no rotation. We also varied the numbers of PCs that were retained for the decoding analysis. We evaluated the resulting decoding accuracy for seven common event-related potential components (N170, mismatch negativity, N2pc, P3b, N400, lateralized readiness potential, and error-related negativity). We also examined more challenging decoding tasks, including decoding of face identity, facial expression, stimulus location, and stimulus orientation. The datasets also varied in the number and density of electrode sites. Our findings indicated that none of the PCA approaches consistently improved decoding performance related to no PCA, and the application of PCA frequently reduced decoding performance. Researchers should therefore be cautious about using PCA prior to decoding EEG data from similar experimental paradigms, populations, and recording setups.
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- 2024
15. Neuropathological findings in Down syndrome, Alzheimer’s disease and control patients with and without SARS-COV-2: preliminary findings
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Granholm, Ann-Charlotte E, Englund, Elisabet, Gilmore, Anah, Head, Elizabeth, Yong, William H, Perez, Sylvia E, Guzman, Samuel J, Hamlett, Eric D, and Mufson, Elliott J
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Biomedical and Clinical Sciences ,Neurosciences ,Intellectual and Developmental Disabilities (IDD) ,Alzheimer's Disease ,Neurodegenerative ,Brain Disorders ,Prevention ,Down Syndrome ,Acquired Cognitive Impairment ,Aging ,Emerging Infectious Diseases ,Infectious Diseases ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Good Health and Well Being ,Humans ,Alzheimer Disease ,COVID-19 ,Male ,Female ,Aged ,Middle Aged ,Brain ,Aged ,80 and over ,Astrocytes ,Amyloid beta-Peptides ,SARS-CoV-2 ,Microglia ,Adult ,tau Proteins ,Corona viruses ,Neurologic symptoms ,Alzheimer's disease ,Glial cells ,Down syndrome ,Alzheimer’s disease ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
The SARS-CoV-2 virus that led to COVID-19 is associated with significant and long-lasting neurologic symptoms in many patients, with an increased mortality risk for people with Alzheimer's disease (AD) and/or Down syndrome (DS). However, few studies have evaluated the neuropathological and inflammatory sequelae in postmortem brain tissue obtained from AD and people with DS with severe SARS-CoV-2 infections. We examined tau, beta-amyloid (Aβ), inflammatory markers and SARS-CoV-2 nucleoprotein in DS, AD, and healthy non-demented controls with COVID-19 and compared with non-infected brain tissue from each disease group (total n = 24). A nested ANOVA was used to determine regional effects of the COVID-19 infection on arborization of astrocytes (Sholl analysis) and percent-stained area of Iba-1 and TMEM 119. SARS-CoV-2 antibodies labeled neurons and glial cells in the frontal cortex of all subjects with COVID-19, and in the hippocampus of two of the three DS COVID-19 cases. SARS-CoV-2-related alterations were observed in peri-vascular astrocytes and microglial cells in the gray matter of the frontal cortex, hippocampus, and para-hippocampal gyrus. Bright field microscopy revealed scattered intracellular and diffuse extracellular Aβ deposits in the hippocampus of controls with confirmed SARS-CoV-2 infections. Overall, the present preliminary findings suggest that SARS-CoV-2 infections induce abnormal inflammatory responses in Down syndrome.
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- 2024
16. A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin
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Casselini, Carolina M, Parson, Henri K, Frizzi, Katie E, Marquez, Alex, Smith, Darrell R, Guernsey, Lucie, Nemmani, Rakesh, Tayarani, Alireza, Jolivalt, Corinne G, Weaver, Jessica, Fernyhough, Paul, Vinik, Aaron I, and Calcutt, Nigel A
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Neurodegenerative ,Peripheral Neuropathy ,Clinical Research ,Chronic Pain ,Diabetes ,Clinical Trials and Supportive Activities ,Pain Research ,Development of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,5.2 Cellular and gene therapies ,Evaluation of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Metabolic and endocrine ,Neurological ,Diabetic neuropathy ,Epidermal nerve fibres ,Muscarinic antagonist ,Neuropathic pain ,Oxybutynin ,Randomized clinical trial ,Animals ,Humans ,Mice ,Rats ,Diabetic Neuropathies ,Diabetes Mellitus ,Experimental ,Diabetes Mellitus ,Type 2 ,Mandelic Acids ,Receptors ,Muscarinic ,Muscarinic Antagonists ,Quality of Life ,Adult ,Diabetes Mellitus ,Type 1 ,Neurology & Neurosurgery - Abstract
Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.
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- 2024
17. A longitudinal MRI and TSPO PET-based investigation of brain region-specific neuroprotection by diazepam versus midazolam following organophosphate-induced seizures
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Hobson, Brad A, Rowland, Douglas J, Dou, Yimeng, Saito, Naomi, Harmany, Zachary T, Bruun, Donald A, Harvey, Danielle J, Chaudhari, Abhijit J, Garbow, Joel R, and Lein, Pamela J
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Biological Psychology ,Biomedical and Clinical Sciences ,Psychology ,Biodefense ,Infectious Diseases ,Brain Disorders ,Epilepsy ,Biomedical Imaging ,Bioengineering ,Neurodegenerative ,Emerging Infectious Diseases ,Neurosciences ,Neurological ,Rats ,Animals ,Diazepam ,Midazolam ,Isoflurophate ,Organophosphates ,Neuroinflammatory Diseases ,Neuroprotection ,Rats ,Sprague-Dawley ,Brain ,Benzodiazepines ,Status Epilepticus ,Positron-Emission Tomography ,Carrier Proteins ,Magnetic Resonance Imaging ,Brain Injuries ,Atrophy ,Diisopropylfluorophosphate ,In vivo imaging ,Neuroinflammation ,Rat ,Status epilepticus ,Pharmacology and Pharmaceutical Sciences ,Neurology & Neurosurgery ,Pharmacology and pharmaceutical sciences ,Biological psychology - Abstract
Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, there are limited data comparing the neuroprotective efficacy of diazepam versus midazolam following acute OP intoxication. To address this data gap, we used non-invasive imaging techniques to longitudinally quantify neuropathology in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) with and without post-exposure intervention with diazepam or midazolam. Magnetic resonance imaging (MRI) was used to monitor neuropathology and brain atrophy, while positron emission tomography (PET) with a radiotracer targeting translocator protein (TSPO) was utilized to assess neuroinflammation. Animals were scanned at 3, 7, 28, 65, 91, and 168 days post-DFP and imaging metrics were quantitated for the hippocampus, amygdala, piriform cortex, thalamus, cerebral cortex and lateral ventricles. In the DFP-intoxicated rat, neuroinflammation persisted for the duration of the study coincident with progressive atrophy and ongoing tissue remodeling. Benzodiazepines attenuated neuropathology in a region-dependent manner, but neither benzodiazepine was effective in attenuating long-term neuroinflammation as detected by TSPO PET. Diffusion MRI and TSPO PET metrics were highly correlated with seizure severity, and early MRI and PET metrics were positively correlated with long-term brain atrophy. Collectively, these results suggest that anti-seizure therapy alone is insufficient to prevent long-lasting neuroinflammation and tissue remodeling.
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- 2024
18. “De novo replication repair deficient glioblastoma, IDH-wildtype” is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade
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Hadad, Sara, Gupta, Rohit, Oberheim Bush, Nancy Ann, Taylor, Jennie W, Villanueva-Meyer, Javier E, Young, Jacob S, Wu, Jasper, Ravindranathan, Ajay, Zhang, Yalan, Warrier, Gayathri, McCoy, Lucie, Shai, Anny, Pekmezci, Melike, Perry, Arie, Bollen, Andrew W, Phillips, Joanna J, Braunstein, Steve E, Raleigh, David R, Theodosopoulos, Philip, Aghi, Manish K, Chang, Edward F, Hervey-Jumper, Shawn L, Costello, Joseph F, de Groot, John, Butowski, Nicholas A, Clarke, Jennifer L, Chang, Susan M, Berger, Mitchel S, Molinaro, Annette M, and Solomon, David A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Cancer ,Cancer ,Precision Medicine ,Brain Disorders ,Genetics ,Human Genome ,Clinical Research ,Cancer Genomics ,Neurosciences ,Immunotherapy ,Orphan Drug ,Rare Diseases ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Adult ,Humans ,Child ,Middle Aged ,Aged ,Glioblastoma ,Immune Checkpoint Inhibitors ,Homozygote ,Prospective Studies ,Brain Neoplasms ,Sequence Deletion ,Mutation ,Isocitrate Dehydrogenase ,Giant cell glioblastoma ,Hypermutation ,Ultrahypermutation ,Mismatch repair deficiency ,POLE ,Lynch syndrome ,Immune checkpoint blockade ,Molecular neuropathology ,Molecular neuro-oncology ,Neurology & Neurosurgery - Abstract
Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p
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- 2024
19. Network state transitions during cortical development
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Wu, Michelle W, Kourdougli, Nazim, and Portera-Cailliau, Carlos
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Biomedical and Clinical Sciences ,Neurosciences ,Neurodegenerative ,Underpinning research ,1.1 Normal biological development and functioning ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Mammalian cortical networks are active before synaptogenesis begins in earnest, before neuronal migration is complete, and well before an animal opens its eyes and begins to actively explore its surroundings. This early activity undergoes several transformations during development. The most important of these is a transition from episodic synchronous network events, which are necessary for patterning the neocortex into functionally related modules, to desynchronized activity that is computationally more powerful and efficient. Network desynchronization is perhaps the most dramatic and abrupt developmental event in an otherwise slow and gradual process of brain maturation. In this Review, we summarize what is known about the phenomenology of developmental synchronous activity in the rodent neocortex and speculate on the mechanisms that drive its eventual desynchronization. We argue that desynchronization of network activity is a fundamental step through which the cortex transitions from passive, bottom-up detection of sensory stimuli to active sensory processing with top-down modulation.
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- 2024
20. Cholinergic Neurotransmission Controls Orexigenic Endocannabinoid Signaling in the Gut in Diet-Induced Obesity.
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Wood, Courtney P, Alvarez, Camila, and DiPatrizio, Nicholas V
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Nutrition ,Neurosciences ,Obesity ,Digestive Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Oral and gastrointestinal ,Stroke ,Cardiovascular ,Metabolic and endocrine ,Animals ,Endocannabinoids ,Male ,Mice ,Synaptic Transmission ,Mice ,Inbred C57BL ,Diet ,High-Fat ,Signal Transduction ,Glycerides ,Arachidonic Acids ,Eating ,Muscarinic Antagonists ,Receptors ,Muscarinic ,Brain-Gut Axis ,cholinergic ,endocannabinoid ,gut–brain ,intestine ,obesity ,parasympathetic ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
The brain bidirectionally communicates with the gut to control food intake and energy balance, which becomes dysregulated in obesity. For example, endocannabinoid (eCB) signaling in the small-intestinal (SI) epithelium is upregulated in diet-induced obese (DIO) mice and promotes overeating by a mechanism that includes inhibiting gut-brain satiation signaling. Upstream neural and molecular mechanism(s) involved in overproduction of orexigenic gut eCBs in DIO, however, are unknown. We tested the hypothesis that overactive parasympathetic signaling at the muscarinic acetylcholine receptors (mAChRs) in the SI increases biosynthesis of the eCB, 2-arachidonoyl-sn-glycerol (2-AG), which drives hyperphagia via local CB1Rs in DIO. Male mice were maintained on a high-fat/high-sucrose Western-style diet for 60 d, then administered several mAChR antagonists 30 min prior to tissue harvest or a food intake test. Levels of 2-AG and the activity of its metabolic enzymes in the SI were quantitated. DIO mice, when compared to those fed a low-fat/no-sucrose diet, displayed increased expression of cFos protein in the dorsal motor nucleus of the vagus, which suggests an increased activity of efferent cholinergic neurotransmission. These mice exhibited elevated levels of 2-AG biosynthesis in the SI, that was reduced to control levels by mAChR antagonists. Moreover, the peripherally restricted mAChR antagonist, methylhomatropine bromide, and the peripherally restricted CB1R antagonist, AM6545, reduced food intake in DIO mice for up to 24 h but had no effect in mice conditionally deficient in SI CB1Rs. These results suggest that hyperactivity at mAChRs in the periphery increases formation of 2-AG in the SI and activates local CB1Rs, which drives hyperphagia in DIO.
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- 2024
21. Older adults use fewer muscles to overcome perturbations during a seated locomotor task
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Shirazi, Seyed Yahya and Huang, Helen J
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Applied and Developmental Psychology ,Biological Psychology ,Health Sciences ,Sports Science and Exercise ,Psychology ,Aging ,Physical Rehabilitation ,Clinical Research ,Rehabilitation ,aging ,motor adaptation ,use-dependent learning ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences - Abstract
Locomotor perturbations provide insights into the human's response to motor errors. We investigated the differences in motor adaptation and muscle co-contraction between young and older adults during perturbed arms and legs recumbent stepping. We hypothesized that besides prolonged adaptation due to use-dependent learning, older adults would exhibit greater muscle co-contraction than young adults in response to the perturbations. Perturbations were brief increases in resistance applied during each stride at the extension-onset or mid-extension of the left or right leg. Seventeen young adults and eleven older adults completed four 10-minute perturbed stepping tasks. Subjects were instructed to follow a visual pacing cue, step smoothly, and use all their limbs to drive the stepper. Results showed that young and older adults did not decrease their errors with more perturbation experience, and errors did not wash out after perturbations were removed. Interestingly, older adults consistently had smaller motor errors than young adults in response to the perturbations. Older adults used fewer muscles to drive the stepper and had greater co-contraction than young adults. The results suggest that despite similar motor error responses, young and older adults use distinctive muscle recruitment patterns to perform the motor task. Age-related motor strategies help track motor changes across the human lifespan and are a baseline for rehabilitation and performance assessment.
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- 2024
22. Cover Image, Volume 72, Issue 5
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Martellucci, Stefano, Flütsch, Andreas, Carter, Mark, Norimoto, Masaki, Pizzo, Donald, Mantuano, Elisabetta, Sadri, Mahrou, Wang, Zixuan, Chillin‐Fuentes, Daisy, Rosenthal, Sara Brin, Azmoon, Pardis, Gonias, Steven L, and Campana, Wendy M
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Biomedical and Clinical Sciences ,Neurosciences ,Neurology & Neurosurgery - Published
- 2024
23. Interferon-β deficiency alters brain response to chronic HIV-1 envelope protein exposure in a transgenic model of NeuroHIV
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Singh, Hina, Koury, Jeffrey, Maung, Ricky, Roberts, Amanda J, and Kaul, Marcus
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Biomedical and Clinical Sciences ,Biological Psychology ,Immunology ,Medical Microbiology ,Psychology ,Genetics ,Sexually Transmitted Infections ,Behavioral and Social Science ,Brain Disorders ,Basic Behavioral and Social Science ,Acquired Cognitive Impairment ,Neurodegenerative ,Mental Health ,Women's Health ,Infectious Diseases ,Neurosciences ,HIV/AIDS ,Underpinning research ,1.1 Normal biological development and functioning ,Mental health ,Neurological ,Animals ,Female ,Male ,Mice ,Brain ,HIV Infections ,HIV-1 ,Interferon-beta ,Mice ,Transgenic ,Interferon beta ,IFN beta knockout ,HIVgp120-transgenic ,HIV associated neurocognitive disorder ,Behavior deficits ,P38 MAPK ,ERK1/2 signaling ,Sexual dimorphism ,IFNβ knockout ,Neurology & Neurosurgery ,Biological psychology - Abstract
Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and β. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNβ (IFNβKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, in cerebral cortex of IFNβKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNβKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNβ-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNβKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNβ on multiple components with more pronounced changes in IFNβKO females. In contrast, the effects of IFNβKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNβ impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNβ plays a vital role in maintaining neuronal homeostasis and memory function.
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- 2024
24. Cell-type-specific expression of tRNAs in the brain regulates cellular homeostasis
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Kapur, Mridu, Molumby, Michael J, Guzman, Carlos, Heinz, Sven, and Ackerman, Susan L
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Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Genetics ,Underpinning research ,1.1 Normal biological development and functioning ,Neurological ,Animals ,RNA ,Transfer ,Homeostasis ,Mice ,Brain ,Neurons ,RNA Polymerase III ,Mice ,Transgenic ,ChIP ,Gtpbp2 ,arginine ,cerebellum ,isodecoder ,isoleucine ,neurodegeneration ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Defects in tRNA biogenesis are associated with multiple neurological disorders, yet our understanding of these diseases has been hampered by an inability to determine tRNA expression in individual cell types within a complex tissue. Here, we developed a mouse model in which RNA polymerase III is conditionally epitope tagged in a Cre-dependent manner, allowing us to accurately profile tRNA expression in any cell type in vivo. We investigated tRNA expression in diverse nervous system cell types, revealing dramatic heterogeneity in the expression of tRNA genes between populations. We found that while maintenance of levels of tRNA isoacceptor families is critical for cellular homeostasis, neurons are differentially vulnerable to insults to distinct tRNA isoacceptor families. Cell-type-specific translatome analysis suggests that the balance between tRNA availability and codon demand may underlie such differential resilience. Our work provides a platform for investigating the complexities of mRNA translation and tRNA biology in the brain.
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- 2024
25. Cisplatin induces BDNF downregulation in middle-aged female rat model while BDNF enhancement attenuates cisplatin neurotoxicity
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Lomeli, Naomi, Pearre, Diana C, Cruz, Maureen, Di, Kaijun, Ricks-Oddie, Joni L, and Bota, Daniela A
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Biological Psychology ,Biomedical and Clinical Sciences ,Psychology ,Neurodegenerative ,Basic Behavioral and Social Science ,Behavioral and Social Science ,Neurosciences ,Mental Health ,Cancer ,Mental health ,Neurological ,Rats ,Animals ,Female ,Cisplatin ,Brain-Derived Neurotrophic Factor ,Rats ,Sprague-Dawley ,Down-Regulation ,Quality of Life ,Riluzole ,Hippocampus ,Disks Large Homolog 4 Protein ,Ampakine ,BDNF ,cancer-related cognitive impairments (CRCI ,Chemobrain) ,Hippocampal neurons ,Neurotoxicity ,Ovarian cancer ,PSD-95 ,Clinical Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Cancer-related cognitive impairments (CRCI) are neurological complications associated with cancer treatment, and greatly affect cancer survivors' quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning and memory. The reduction of BDNF is associated with the decrease in cognitive function in various neurological disorders. Few pre-clinical studies have reported on the effects of chemotherapy and medical stress on BDNF levels and cognition. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive function in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected 24 weeks after cisplatin initiation. In cultured hippocampal neurons, we screened three neuroprotective agents, riluzole (an approved treatment for amyotrophic lateral sclerosis), as well as the ampakines CX546 and CX1739. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD-95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD-95. Ampakines (CX546 and CX1739) and riluzole did not affect the antitumor efficacy of cisplatin in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels on cognitive function, although future studies are warranted to assess the efficacy of BDNF enhancement in vivo on synaptic plasticity. Collectively, our results indicate that cancer treatment exerts long-lasting changes in BDNF levels, and support BDNF enhancement as a potential preventative approach to target CRCI with therapeutics that are FDA approved and/or in clinical study for other indications.
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- 2024
26. A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury
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Yuan, Nina Y, Medders, Kathryn E, Sanchez, Ana B, Shah, Rohan, de Rozieres, Cyrus M, Ojeda-Juárez, Daniel, Maung, Ricky, Williams, Roy, Gelman, Benjamin B, Baaten, Bas J, Roberts, Amanda J, and Kaul, Marcus
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Acquired Cognitive Impairment ,Sexually Transmitted Infections ,Infectious Diseases ,Neurodegenerative ,Neurosciences ,HIV/AIDS ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Neurological ,Mice ,Humans ,Animals ,HIV-1 ,Macrophages ,Leukotrienes ,Neurons ,p38 Mitogen-Activated Protein Kinases ,Mice ,Transgenic ,HIV Infections ,Cysteine ,HIV ,Neurotoxicity ,Cysteinyl leukotrienes ,Knockout ,HIVgp120-transgenic ,HIV associated neurocognitive disorder ,Behavior deficits ,P38 MAPK ,ERK1/2 signaling ,Psychology ,Neurology & Neurosurgery ,Biological psychology - Abstract
Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury.
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- 2024
27. Quantitative T2 mapping-based longitudinal assessment of brain injury and therapeutic rescue in the rat following acute organophosphate intoxication
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Almeida, Alita Jesal D, Hobson, Brad A, Saito, Naomi, Bruun, Donald A, Porter, Valerie A, Harvey, Danielle J, Garbow, Joel R, Chaudhari, Abhijit J, and Lein, Pamela J
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Neurodegenerative ,Biomedical Imaging ,Neurosciences ,Prevention ,Brain Disorders ,5.1 Pharmaceuticals ,Neurological ,Rats ,Male ,Animals ,Rats ,Sprague-Dawley ,Isoflurophate ,Organophosphates ,Cholinesterase Inhibitors ,Organophosphate Poisoning ,Brain Injuries ,Brain ,Midazolam ,Allopregnanolone ,Diisopropylfluorophosphate ,Magnetic resonance imaging ,Neurosteroid ,T 2 mapping ,T(2) mapping ,Psychology ,Neurology & Neurosurgery ,Pharmacology and pharmaceutical sciences ,Biological psychology - Abstract
Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.
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- 2024
28. Axon‐derived PACSIN1 binds to the Schwann cell survival receptor, LRP1, and transactivates TrkC to promote gliatrophic activities
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Martellucci, Stefano, Flütsch, Andreas, Carter, Mark, Norimoto, Masaki, Pizzo, Donald, Mantuano, Elisabetta, Sadri, Mahrou, Wang, Zixuan, Chillin‐Fuentes, Daisy, Rosenthal, Sara Brin, Azmoon, Pardis, Gonias, Steven L, and Campana, Wendy M
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Biomedical and Clinical Sciences ,Neurosciences ,Regenerative Medicine ,Physical Injury - Accidents and Adverse Effects ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Mice ,Rats ,Axons ,Cell Survival ,Cells ,Cultured ,Ligands ,Rats ,Sprague-Dawley ,Receptor Protein-Tyrosine Kinases ,Schwann Cells ,Humans ,Adaptor Proteins ,Signal Transducing ,Recombinant Proteins ,axon glia interaction ,cell signaling ,injury-repair ,LRP1 ,Schwann cells ,Neurology & Neurosurgery - Abstract
Schwann cells (SCs) undergo phenotypic transformation and then orchestrate nerve repair following PNS injury. The ligands and receptors that activate and sustain SC transformation remain incompletely understood. Proteins released by injured axons represent important candidates for activating the SC Repair Program. The low-density lipoprotein receptor-related protein-1 (LRP1) is acutely up-regulated in SCs in response to injury, activating c-Jun, and promoting SC survival. To identify novel LRP1 ligands released in PNS injury, we applied a discovery-based approach in which extracellular proteins in the injured nerve were captured using Fc-fusion proteins containing the ligand-binding motifs of LRP1 (CCR2 and CCR4). An intracellular neuron-specific protein, Protein Kinase C and Casein Kinase Substrate in Neurons (PACSIN1) was identified and validated as an LRP1 ligand. Recombinant PACSIN1 activated c-Jun and ERK1/2 in cultured SCs. Silencing Lrp1 or inhibiting the LRP1 cell-signaling co-receptor, the NMDA-R, blocked the effects of PACSIN1 on c-Jun and ERK1/2 phosphorylation. Intraneural injection of PACSIN1 into crush-injured sciatic nerves activated c-Jun in wild-type mice, but not in mice in which Lrp1 is conditionally deleted in SCs. Transcriptome profiling of SCs revealed that PACSIN1 mediates gene expression events consistent with transformation to the repair phenotype. PACSIN1 promoted SC migration and viability following the TNFα challenge. When Src family kinases were pharmacologically inhibited or the receptor tyrosine kinase, TrkC, was genetically silenced or pharmacologically inhibited, PACSIN1 failed to induce cell signaling and prevent SC death. Collectively, these studies demonstrate that PACSIN1 is a novel axon-derived LRP1 ligand that activates SC repair signaling by transactivating TrkC.
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- 2024
29. Fully automated whole brain segmentation from rat MRI scans with a convolutional neural network
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Porter, Valerie A, Hobson, Brad A, Foster, Brent, Lein, Pamela J, and Chaudhari, Abhijit J
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Biomedical and Clinical Sciences ,Neurosciences ,Dementia ,Alzheimer's Disease ,Machine Learning and Artificial Intelligence ,Networking and Information Technology R&D (NITRD) ,Neurodegenerative ,Aging ,Bioengineering ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Biomedical Imaging ,Brain Disorders ,Neurological ,Rats ,Animals ,Image Processing ,Computer-Assisted ,Neural Networks ,Computer ,Brain ,Magnetic Resonance Imaging ,Neuroimaging ,Alzheimer Disease ,Automated Segmentation ,Machine Learning ,Preclinical Neuroimaging ,Rodent Brain Imaging ,MRI ,Skull Stripping ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
BackgroundWhole brain delineation (WBD) is utilized in neuroimaging analysis for data preprocessing and deriving whole brain image metrics. Current automated WBD techniques for analysis of preclinical brain MRI data show limited accuracy when images present with significant neuropathology and anatomical deformations, such as that resulting from organophosphate intoxication (OPI) and Alzheimer's Disease (AD), and inadequate generalizability.MethodsA modified 2D U-Net framework was employed for WBD of MRI rodent brains, consisting of 27 convolutional layers, batch normalization, two dropout layers and data augmentation, after training parameter optimization. A total of 265 T2-weighted 7.0 T MRI scans were utilized for the study, including 125 scans of an OPI rat model for neural network training. For testing and validation, 20 OPI rat scans and 120 scans of an AD rat model were utilized. U-Net performance was evaluated using Dice coefficients (DC) and Hausdorff distances (HD) between the U-Net-generated and manually segmented WBDs.ResultsThe U-Net achieved a DC (median[range]) of 0.984[0.936-0.990] and HD of 1.69[1.01-6.78] mm for OPI rat model scans, and a DC (mean[range]) of 0.975[0.898-0.991] and HD of 1.49[0.86-3.89] for the AD rat model scans.Comparison with existing methodsThe proposed approach is fully automated and robust across two rat strains and longitudinal brain changes with a computational speed of 8 seconds/scan, overcoming limitations of manual segmentation.ConclusionsThe modified 2D U-Net provided a fully automated, efficient, and generalizable segmentation approach that achieved high accuracy across two disparate rat models of neurological diseases.
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- 2024
30. Association Between Preoperative Delirium and Plasma Biomarkers of Neuropathology Following Acute Hip Fracture: Hip Fracture Inpatient Pathophysiology Study (HIPS) Pilot (P8-15.002)
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Berry, Ketura, Youn, Joy, Rojas-Martinez, Julio, VandeVrede, Lawren, Castro, David, Diaz, Stephanie Roa, Garcia, Thelma, Degesys, Nida, Boscardin, John, Covinsky, Kenneth, Rogers, Stephanie, Newman, John, Miller, Bruce, Boxer, Adam, Douglas, Vanja, and LaHue, Sara
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Biomedical and Clinical Sciences ,Clinical Sciences ,Neurosciences ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Published
- 2024
31. Statin treatment intensity and cerebral vasomotor reactivity response in patients with ischemic stroke
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Sabayan, Behnam, Sigari, Amirhossein Akhavan, Modir, Royya, Meyer, Brett C, Hemmen, Thomas, Meyer, Dawn, and Shahripour, Reza Bavarsad
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Biomedical and Clinical Sciences ,Clinical Sciences ,Aging ,Clinical Research ,Brain Disorders ,Cardiovascular ,Stroke ,Neurosciences ,breath-holding index ,statin ,stroke ,transcranial Doppler ,vasomotor reactivity ,breath‐holding index ,Neurology & Neurosurgery ,Clinical sciences ,Biological psychology - Abstract
Background and purposeCerebral vasomotor reactivity (VMR) is vital for regulating brain blood flow and maintaining neurological function. Impaired cerebral VMR is linked to a higher risk of stroke and poor post-stroke outcomes. This study explores the relationship between statin treatment intensity and VMR in patients with ischemic stroke.MethodsSeventy-four consecutive patients (mean age 69.3 years, 59.4% male) with recent ischemic stroke were included. VMR levels were assessed 4 weeks after the index stroke using transcranial Doppler, measuring the breath-holding index (BHI) as an indicator of the percentage increase in middle cerebral artery blood flow (higher BHI signifies higher VMR). Multistep multivariable regression models, adjusted for demographic and cerebrovascular risk factors, were employed to examine the association between statin intensity treatment and BHI levels.ResultsForty-one patients (55%) received high-intensity statins. Patients receiving high-intensity statins exhibited a mean BHI of 0.85, whereas those on low-intensity statins had a mean BHI of 0.67 (mean difference 0.18, 95% confidence interval: 0.13-0.22, p-value.05). Furthermore, no significant association was found between baseline low-density lipoprotein (LDL) levels and BHI.ConclusionsHigh-intensity statin treatment post-ischemic stroke is linked to elevated VMR independent of demographic and clinical characteristics, including baseline LDL level. Further research is needed to explore statin therapy's impact on preserving brain vascular function beyond lipid-lowering effects.
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- 2024
32. Clinical dimensions along the non-fluent variant primary progressive aphasia spectrum
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Illán-Gala, Ignacio, Lorca-Puls, Diego L, Tee, Boon Lead, Ezzes, Zoe, de Leon, Jessica, Miller, Zachary A, Rubio-Guerra, Sara, Santos-Santos, Miguel, Gómez-Andrés, David, Grinberg, Lea T, Spina, Salvatore, Kramer, Joel H, Wauters, Lisa D, Henry, Maya L, Boxer, Adam L, Rosen, Howard J, Miller, Bruce L, Seeley, William W, Mandelli, Maria Luisa, and Gorno-Tempini, Maria Luisa
- Subjects
Biological Psychology ,Psychology ,Aphasia ,Neurodegenerative ,Neurosciences ,Brain Disorders ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Humans ,Aphasia ,Broca ,Dysarthria ,Apraxias ,Language ,Speech ,Aphasia ,Primary Progressive ,Primary Progressive Nonfluent Aphasia ,apraxia of speech ,dysarthria ,primary progressive aphasia ,corticobasal degeneration ,progressive supranuclear palsy ,magnetic resonance imaging ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences - Abstract
It is debated whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) belong to the same clinical spectrum, traditionally termed non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), or exist as two completely distinct syndromic entities with specific pathologic/prognostic correlates. We analysed speech, language and disease severity features in a comprehensive cohort of patients with progressive motor speech impairment and/or agrammatism to ascertain evidence of naturally occurring, clinically meaningful non-overlapping syndromic entities (e.g. PPAOS and PAA) in our data. We also assessed if data-driven latent clinical dimensions with aetiologic/prognostic value could be identified. We included 98 participants, 43 of whom had an autopsy-confirmed neuropathological diagnosis. Speech pathologists assessed motor speech features indicative of dysarthria and apraxia of speech (AOS). Quantitative expressive/receptive agrammatism measures were obtained and compared with healthy controls. Baseline and longitudinal disease severity was evaluated using the Clinical Dementia Rating Sum of Boxes (CDR-SB). We investigated the data's clustering tendency and cluster stability to form robust symptom clusters and employed principal component analysis to extract data-driven latent clinical dimensions (LCD). The longitudinal CDR-SB change was estimated using linear mixed-effects models. Of the participants included in this study, 93 conformed to previously reported clinical profiles (75 with AOS and agrammatism, 12 PPAOS and six PAA). The remaining five participants were characterized by non-fluent speech, executive dysfunction and dysarthria without apraxia of speech or frank agrammatism. No baseline clinical features differentiated between frontotemporal lobar degeneration neuropathological subgroups. The Hopkins statistic demonstrated a low cluster tendency in the entire sample (0.45 with values near 0.5 indicating random data). Cluster stability analyses showed that only two robust subgroups (differing in agrammatism, executive dysfunction and overall disease severity) could be identified. Three data-driven components accounted for 71% of the variance [(i) severity-agrammatism; (ii) prominent AOS; and (iii) prominent dysarthria]. None of these data-driven LCDs allowed an accurate prediction of neuropathology. The severity-agrammatism component was an independent predictor of a faster CDR-SB increase in all the participants. Higher dysarthria severity, reduced words per minute and expressive and receptive agrammatism severity at baseline independently predicted accelerated disease progression. Our findings indicate that PPAOS and PAA, rather than exist as completely distinct syndromic entities, constitute a clinical continuum. In our cohort, splitting the nfvPPA spectrum into separate clinical phenotypes did not improve clinical-pathological correlations, stressing the need for new biological markers and consensus regarding updated terminology and clinical classification.
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- 2024
33. Monosynaptic rabies tracing reveals sex- and age-dependent dorsal subiculum connectivity alterations in an Alzheimer's disease mouse model.
- Author
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Ye, Qiao, Gast, Gocylen, Wilfley, Erik George, Huynh, Hanh, Hays, Chelsea, Holmes, Todd C, and Xu, Xiangmin
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Biomedical and Clinical Sciences ,Neurosciences ,Aging ,Mental Health ,Neurodegenerative ,Basic Behavioral and Social Science ,Alzheimer's Disease ,Behavioral and Social Science ,Dementia ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,1.1 Normal biological development and functioning ,Underpinning research ,1.2 Psychological and socioeconomic processes ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,Neurological ,Good Health and Well Being ,Hippocampus ,Entorhinal Cortex ,Neurons ,Animals ,Mice ,Rabies ,Alzheimer Disease ,Female ,Male ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Toward a better understanding of AD circuit-based mechanisms, we mapped synaptic circuit inputs to dorsal SUB using monosynaptic rabies tracing in the 5xFAD mouse model by quantitatively comparing the circuit connectivity of SUB excitatory neurons in age-matched controls and 5xFAD mice at different ages for both sexes. Input-mapped brain regions include the hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band, retrosplenial cortex, SUB, postsubiculum (postSUB), visual cortex, auditory cortex, somatosensory cortex, entorhinal cortex, thalamus, perirhinal cortex (Prh), ectorhinal cortex, and temporal association cortex. We find sex- and age-dependent changes in connectivity strengths and patterns of SUB presynaptic inputs from hippocampal subregions and other brain regions in 5xFAD mice compared with control mice. Significant sex differences for SUB inputs are found in 5xFAD mice for CA1, CA2, CA3, postSUB, Prh, lateral entorhinal cortex, and medial entorhinal cortex: all of these areas are critical for learning and memory. Notably, we find significant changes at different ages for visual cortical inputs to SUB. While the visual function is not ordinarily considered defective in AD, these specific connectivity changes reflect that altered visual circuitry contributes to learning and memory deficits. Our work provides new insights into SUB-directed neural circuit mechanisms during AD progression and supports the idea that neural circuit disruptions are a prominent feature of AD.
- Published
- 2024
34. Transcriptomic contributions to a modern cytoarchitectonic parcellation of the human cerebral cortex
- Author
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King, Leana and Weiner, Kevin S
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Biomedical and Clinical Sciences ,Medical Physiology ,Neurosciences ,Cancer ,Brain Disorders ,Digestive Diseases ,Liver Disease ,Genetics ,Liver Cancer ,Rare Diseases ,Underpinning research ,1.1 Normal biological development and functioning ,Neurological ,Cortical thickness ,Cytoarchitecture ,Gradation ,Myelination ,Transcriptomics ,Cognitive Sciences ,Developmental Biology ,Neurology & Neurosurgery ,Medical physiology - Abstract
Transcriptomic contributions to the anatomical, functional, and network layout of the human cerebral cortex (HCC) have become a major interest in cognitive and systems neuroscience. Here, we tested if transcriptomic differences support a modern, algorithmic cytoarchitectonic parcellation of HCC. Using a data-driven approach, we identified a sparse subset of genes that differentially contributed to the cytoarchitectonic parcellation of HCC. A combined metric of cortical thickness and myelination (CT/M ratio), as well as cell density, correlated with gene expression. Enrichment analyses showed that genes specific to the cytoarchitectonic parcellation of the HCC were related to molecular functions such as transmembrane transport and ion channel activity. Together, the relationship between transcriptomics and cytoarchitecture bridges the gap among (i) gradients at the macro-scale (including thickness and myelination), (ii) areas at the meso-scale, and (iii) cell density at the microscale, as well as supports the recently proposed cortical spectrum theory and structural model.
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- 2024
35. GABAergic Inhibition Controls Receptive Field Size, Sensitivity, and Contrast Preference of Direction Selective Retinal Ganglion Cells Near the Threshold of Vision
- Author
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Roy, Suva, Yao, Xiaoyang, Rathinavelu, Jay, and Field, Greg D
- Subjects
Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Eye Disease and Disorders of Vision ,Neurosciences ,Retinal Ganglion Cells ,Gap Junctions ,Inhibition ,Psychological ,Motion ,gamma-Aminobutyric Acid ,adaptation ,electrode array ,retina ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Information about motion is encoded by direction-selective retinal ganglion cells (DSGCs). These cells reliably transmit this information across a broad range of light levels, spanning moonlight to sunlight. Previous work indicates that adaptation to low light levels causes heterogeneous changes to the direction tuning of ON-OFF (oo)DSGCs and suggests that superior-preferring ON-OFF DSGCs (s-DSGCs) are biased toward detecting stimuli rather than precisely signaling direction. Using a large-scale multielectrode array, we measured the absolute sensitivity of ooDSGCs and found that s-DSGCs are 10-fold more sensitive to dim flashes of light than other ooDSGCs. We measured their receptive field (RF) sizes and found that s-DSGCs also have larger receptive fields than other ooDSGCs; however, the size difference does not fully explain the sensitivity difference. Using a conditional knock-out of gap junctions and pharmacological manipulations, we demonstrate that GABA-mediated inhibition contributes to the difference in absolute sensitivity and receptive field size at low light levels, while the connexin36-mediated gap junction coupling plays a minor role. We further show that under scotopic conditions, ooDSGCs exhibit only an ON response, but pharmacologically removing GABA-mediated inhibition unmasks an OFF response. These results reveal that GABAergic inhibition controls and differentially modulates the responses of ooDSGCs under scotopic conditions.
- Published
- 2024
36. Disentangling tau: One protein, many therapeutic approaches
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Lane-Donovan, Courtney and Boxer, Adam L
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Biomedical and Clinical Sciences ,Biological Psychology ,Neurosciences ,Psychology ,Pharmacology and Pharmaceutical Sciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Frontotemporal Dementia (FTD) ,Aging ,Rare Diseases ,Neurodegenerative ,Alzheimer's Disease ,Dementia ,Brain Disorders ,Acquired Cognitive Impairment ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Humans ,tau Proteins ,Alzheimer Disease ,Tauopathies ,Supranuclear Palsy ,Progressive ,Neurodegenerative Diseases ,Tau ,Neurodegeneration ,Alzheimer's disease ,Progressive supranuclear palsy ,Immunotherapy ,Clinical trials ,Public Health and Health Services ,Neurology & Neurosurgery ,Pharmacology and pharmaceutical sciences ,Biological psychology - Abstract
The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction and accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, and progressive supranuclear palsy collectively impact millions of patients and their families worldwide. Despite years of drug development using a variety of mechanisms of action, no therapeutic directed against tau has been approved for clinical use. This raises important questions about our current model of tau pathology and invites thoughtful consideration of our approach to nonclinical models and clinical trial design. In this article, we review what is known about the biology and genetics of tau, placing it in the context of current and failed clinical trials. We highlight potential reasons for the lack of success to date and offer suggestions for new pathways in therapeutic development. Overall, our viewpoint to the future is optimistic for this important group of neurodegenerative diseases.
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- 2024
37. Deep latent variable joint cognitive modeling of neural signals and human behavior
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Vo, Khuong, Sun, Qinhua Jenny, Nunez, Michael D, Vandekerckhove, Joachim, and Srinivasan, Ramesh
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Biomedical and Clinical Sciences ,Health Sciences ,Basic Behavioral and Social Science ,Mental Health ,Brain Disorders ,Neurosciences ,Rehabilitation ,Bioengineering ,Behavioral and Social Science ,Neurological ,Mental health ,Decision making ,Deep learning ,Drift-diffusion model ,EEG ,Latent-variable models ,Neurocognitive model ,Variational Bayes ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences - Abstract
As the field of computational cognitive neuroscience continues to expand and generate new theories, there is a growing need for more advanced methods to test the hypothesis of brain-behavior relationships. Recent progress in Bayesian cognitive modeling has enabled the combination of neural and behavioral models into a single unifying framework. However, these approaches require manual feature extraction, and lack the capability to discover previously unknown neural features in more complex data. Consequently, this would hinder the expressiveness of the models. To address these challenges, we propose a Neurocognitive Variational Autoencoder (NCVA) to conjoin high-dimensional EEG with a cognitive model in both generative and predictive modeling analyses. Importantly, our NCVA enables both the prediction of EEG signals given behavioral data and the estimation of cognitive model parameters from EEG signals. This novel approach can allow for a more comprehensive understanding of the triplet relationship between behavior, brain activity, and cognitive processes.
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- 2024
38. Cannabidiol as a potential cessation therapeutic: Effects on intravenous nicotine self-administration and withdrawal symptoms in mice
- Author
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Cheeks, Samantha N, Buzzi, Belle, Valdez, Ashley, Mogul, Allison S, Damaj, M Imad, and Fowler, Christie D
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Brain Disorders ,Behavioral and Social Science ,Therapeutic Cannabinoid Research ,Drug Abuse (NIDA only) ,Substance Misuse ,Prevention ,Cannabidiol Research ,Tobacco Smoke and Health ,Cannabinoid Research ,Tobacco ,Good Health and Well Being ,Mice ,Male ,Female ,Animals ,Nicotine ,Cannabidiol ,Smoking ,Substance Withdrawal Syndrome ,Smoking Cessation ,Intravenous nicotine self -administration ,Tobacco addiction ,E -cigarette ,Therapeutic ,Withdrawal ,E-cigarette ,Intravenous nicotine self-administration ,Neurosciences ,Neurology & Neurosurgery ,Pharmacology and pharmaceutical sciences ,Biological psychology - Abstract
Cigarette smoking remains a leading cause of preventable disease and death worldwide. Due to the devastating negative health effects of smoking, many users attempt to quit, but few are successful in the long-term. Thus, there is a critical need for novel therapeutic approaches. In these investigations, we sought to examine whether cannabidiol (CBD) has the potential to be repurposed as a nicotine cessation therapeutic. In the first study, male and female mice were trained to respond for intravenous nicotine infusions at either a low or moderate nicotine dose and then were pretreated with CBD prior to their drug-taking session. We found that CBD produced a significant decrease in the number of nicotine rewards earned, and this effect was evidenced across CBD doses and with both the low and moderate levels of nicotine intake. These effects on drug intake were not due to general motor-related effects, since mice self-administering food pellets did not alter their behavior with CBD administration. The potential effects of CBD in mitigating nicotine withdrawal symptoms were then investigated. We found that CBD attenuated the somatic signs of nicotine withdrawal and prevented nicotine's hyperalgesia-inducing effects. Taken together, these results demonstrate that modulation of cannabinoid signaling may be a viable therapeutic option as a smoking cessation aid.
- Published
- 2024
39. Habitual Sleep Duration and Health-Related Quality of Life in Family Caregivers: Findings from the Behavioral Risk Factor Surveillance System
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Ogugu, Everlyne G, Reilly, Maura R, Anne, Kougang T, and Bell, Janice F
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Health Services and Systems ,Public Health ,Health Sciences ,Basic Behavioral and Social Science ,Mental Health ,Sleep Research ,Behavioral and Social Science ,Prevention ,Clinical Research ,Good Health and Well Being ,Clinical Sciences ,Psychology ,Neurology & Neurosurgery ,Public health ,Biological psychology ,Clinical and health psychology - Abstract
BackgroundInsufficient sleep duration is associated with poor health-related quality of life (HRQoL). However, this relationship has not been studied in family caregivers, a group at high risk of insufficient sleep duration and poor HRQoL.ObjectiveTo examine the associations between habitual sleep duration and HRQoL measures in family caregivers.MethodsThis cross-sectional study used data from 23,321 caregivers in the 2016 Behavioral Risk Factor Surveillance System. The HRQoL measures were health status and poor mental and physical health days. A multivariable logistic regression model was used to assess the association between sleep duration (9 hours) and health status (fair or poor versus good to excellent). Zero-inflated negative binomial models were used to analyze the association of sleep duration with poor mental and physical health days.ResultsFair or poor health status was significantly higher in caregivers with short (odds ratio [OR], 1.40; 95% CI: 1.12, 1.74) and long (OR, 2.07; 95% CI: 1.34, 3.21) sleep duration. Short sleep duration was associated with a higher number of poor mental health days (IRR [incident rate ratio], 1.17; 95% CI: 1.04, 1.31) and poor physical health days (IRR, 1.26; 95% CI: 1.10, 1.45). Long sleep duration was associated with more poor mental health days (IRR, 1.31; 95% CI: 1.08, 1.60).ConclusionExtremes in sleep duration were associated with lower HRQoL. These findings point to the need for interventions that promote adequate sleep and address factors underlying extremes in sleep duration in the context of family caregiving.
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- 2024
40. Local synaptic inhibition mediates cerebellar granule cell pattern separation and enables learned sensorimotor associations
- Author
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Fleming, Elizabeth A, Field, Greg D, Tadross, Michael R, and Hull, Court
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Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Behavioral and Social Science ,Underpinning research ,1.1 Normal biological development and functioning ,Neurological ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
The cerebellar cortex has a key role in generating predictive sensorimotor associations. To do so, the granule cell layer is thought to establish unique sensorimotor representations for learning. However, how this is achieved and how granule cell population responses contribute to behavior have remained unclear. To address these questions, we have used in vivo calcium imaging and granule cell-specific pharmacological manipulation of synaptic inhibition in awake, behaving mice. These experiments indicate that inhibition sparsens and thresholds sensory responses, limiting overlap between sensory ensembles and preventing spiking in many granule cells that receive excitatory input. Moreover, inhibition can be recruited in a stimulus-specific manner to powerfully decorrelate multisensory ensembles. Consistent with these results, granule cell inhibition is required for accurate cerebellum-dependent sensorimotor behavior. These data thus reveal key mechanisms for granule cell layer pattern separation beyond those envisioned by classical models.
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- 2024
41. Harnessing Brain Pathology for Dementia Prevention
- Author
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Leng, Yue and Yaffe, Kristine
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Published
- 2024
42. Abstract TMP39: Paucity of Evidence-Based Patent Foramen Ovale Severity Ratings in Transesophageal Echocardiogram Clinical Reports
- Author
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Sun, Philip Y, Tobis, Jonathan M, Liebeskind, David S, Alfonso, Rodel C, and Saver, Jeffrey L
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Trials and Supportive Activities ,Brain Disorders ,Cerebrovascular ,Clinical Research ,Stroke ,Neurosciences ,Cardiorespiratory Medicine and Haematology ,Neurology & Neurosurgery ,Clinical sciences ,Allied health and rehabilitation science - Abstract
Introduction: The presence of a large physiologic shunt, defined as >20 left atrial microbubbles within 3 cardiac cycles on transesophageal echocardiography (TEE), is a key, randomized controlled trial-validated, indication for patent foramen ovale (PFO) with a closure device in patients with otherwise cryptogenic ischemic stroke. The frequency with which this information is available to treating physicians from clinical TEE reports has not been well delineated. Methods: Among consecutive ischemic stroke patients admitted to an academic medical center undergoing TEE between January-June 2023, TEE reports were reviewed to determine frequency with which formal, clinical-trial definition-adherent characterization of PFO shunt size was provided, frequency of informal PFO shunt size descriptions, and correlations with transcranial Doppler (TCD) formal shunt grades (Spencer Grades 1-5). Results: Among the 50 patients, median age was 64 (IQR 58-74.5), and 20 (40%) were female. On TEE, shunt presence was assessed by bubble study in 38 (76%), direct Doppler alone in 6 (12%), and neither in 6 (12%). Among patients with bubble study, a right-to-left shunt (RLS) potentially due to PFO was present 15 (39%). RLS severity was quantified in 27% (4/15) of PFO patients, all with formally small (
- Published
- 2024
43. Insomnia and behaviorally induced sleep syndrome in undergraduates tested during the COVID-19 pandemic: associations with health, stress, and GPA.
- Author
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Lukowski, Angela F, Kamliot, Deborah Z, and Schlaupitz, Caleb A
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Behavioral and Social Science ,Basic Behavioral and Social Science ,Sleep Research ,Cardiovascular ,Clinical Research ,Good Health and Well Being ,Humans ,Sleep Initiation and Maintenance Disorders ,COVID-19 ,Pandemics ,Sleep ,Sleep Deprivation ,Syndrome ,sleep ,insomnia ,health ,stress ,Other Medical and Health Sciences ,Psychology ,Neurology & Neurosurgery ,Clinical sciences - Abstract
Study objectivesThis study was conducted to determine (1) whether the distribution of undergraduates who endorse insomnia or behaviorally induced insufficient sleep syndrome (BIISS) varied during the coronavirus disease 2019 (COVID-19) pandemic relative to normal sleepers and in comparison to values reported pre-pandemic and (2) whether group (insomnia, BIISS, and normal sleepers) was differentially associated with health, stress, and academic achievement mid-pandemic.MethodsTwo hundred ninety-three undergraduates completed online questionnaires assessing demographics, global sleep quality, insomnia severity, health, and perceived stress; cumulative grade point averages (GPAs) were also collected for each participant.ResultsThe proportion of participants in each group did not differ from the pre-pandemic values reported in Williams et al (2020). Relative to the normal-sleepers group, the insomnia group reported poorer sleep quality, greater insomnia severity, poorer functioning on measures of physical health, and increased stress; only 1 significant difference was found concerning the BIISS group. Group differences were not found on GPA.ConclusionsDespite the various challenges brought about by the COVID-19 pandemic, the distribution of participants by group was similar to those reported pre-pandemic. The insomnia group fared most poorly in terms of sleep quality, insomnia severity, physical health, and stress. As such, additional effort should be devoted to identifying undergraduates with insomnia to provide treatment that may improve their sleep and their health.CitationLukowski AF, Kamliot DZ, Schlaupitz CA. Insomnia and behaviorally induced sleep syndrome in undergraduates tested during the COVID-19 pandemic: associations with health, stress, and GPA. J Clin Sleep Med. 2024;20(2):261-269.
- Published
- 2024
44. The effect of sevoflurane exposure on cell-type-specific changes in the prefrontal cortex in young mice.
- Author
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Zhao, Bao-Jian, Song, Shao-Yong, Zhao, Wei-Ming, Xu, Han-Bing, Peng, Ke, Shan, Xi-Sheng, Chen, Qing-Cai, Liu, Hong, Liu, Hua-Yue, and Ji, Fu-Hai
- Subjects
developmental sevoflurane neurotoxicity ,prefrontal cortex ,single-nucleus RNA sequencing ,Biochemistry and Cell Biology ,Neurosciences ,Neurology & Neurosurgery ,Biochemistry and cell biology - Abstract
Sevoflurane, the predominant pediatric anesthetic, has been linked to neurotoxicity in young mice, although the underlying mechanisms remain unclear. This study focuses on investigating the impact of neonatal sevoflurane exposure on cell-type-specific alterations in the prefrontal cortex (PFC) of young mice. Neonatal mice were subjected to either control treatment (60% oxygen balanced with nitrogen) or sevoflurane anesthesia (3% sevoflurane in 60% oxygen balanced with nitrogen) for 2 hours on postnatal days (PNDs) 6, 8, and 10. Behavioral tests and single-nucleus RNA sequencing (snRNA-seq) of the PFC were conducted from PNDs 31 to 37. Mechanistic exploration included clustering analysis, identification of differentially expressed genes (DEGs), enrichment analyses, single-cell trajectory analysis, and genome-wide association studies (GWAS). Sevoflurane anesthesia resulted in sociability and cognition impairments in mice. Novel specific marker genes identified 8 distinct cell types in the PFC. Most DEGs between the control and sevoflurane groups were unique to specific cell types. Re-defining 15 glutamatergic neuron subclusters based on layer identity revealed their altered expression profiles. Notably, sevoflurane disrupted the trajectory from oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). Validation of disease-relevant candidate genes across the main cell types demonstrated their association with social dysfunction and working memory impairment. Behavioral results and snRNA-seq collectively elucidated the cellular atlas in the PFC of young male mice, providing a foundation for further mechanistic studies on developmental neurotoxicity induced by anesthesia.
- Published
- 2024
45. Cadherin-13 Maintains Retinotectal Synapses via Transneuronal Interactions
- Author
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Matcham, Angela C, Toma, Kenichi, Tsai, Nicole Y, Sze, Christina J, Lin, Pin-Yeh, Stewart, Ilaria F, and Duan, Xin
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Eye Disease and Disorders of Vision ,1.1 Normal biological development and functioning ,Neurological ,Animals ,Retinal Ganglion Cells ,Synapses ,Superior Colliculi ,Dendrites ,Cadherins ,Mammals ,cadherin ,dendritic spine ,neuron types ,retinal ganglion cells ,superior colliculus ,synaptic choice ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Maintaining precise synaptic contacts between neuronal partners is critical to ensure the proper functioning of the mammalian central nervous system (CNS). Diverse cell recognition molecules, such as classic cadherins (Cdhs), are part of the molecular machinery mediating synaptic choices during development and synaptic maintenance. Yet, the principles governing neuron-neuron wiring across diverse CNS neuron types remain largely unknown. The retinotectal synapses, connections from the retinal ganglion cells (RGCs) to the superior collicular (SC) neurons, offer an ideal experimental system to reveal molecular logic underlying synaptic choices and formation. This is due to the retina's unidirectional and laminar-restricted projections to the SC and the large databases of presynaptic RGC subtypes and postsynaptic SC neuronal types. Here, we focused on determining the role of Type II Cdhs in wiring the retinotectal synapses. We surveyed Cdhs expression patterns at neuronal resolution and revealed that Cdh13 is enriched in the wide-field neurons in the superficial SC (sSC). In either the Cdh13 null mutant or selective adult deletion within the wide-field neurons, there is a significant reduction of spine densities in the distal dendrites of these neurons in both sexes. Additionally, Cdh13 removal from presynaptic RGCs reduced dendritic spines in the postsynaptic wide-field neurons. Cdh13-expressing RGCs use differential mechanisms than αRGCs and On-Off Direction-Selective Ganglion Cells (ooDSGCs) to form specific retinotectal synapses. The results revealed a selective transneuronal interaction mediated by Cdh13 to maintain proper retinotectal synapses in vivo.
- Published
- 2024
46. Neuromodulation for primary headache disorders: Advantages and challenges
- Author
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Jicha, Crystal and Pham, Kendra
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,cluster ,debate ,migraine ,neuromodulation ,nonpharmacologic ,Humans ,Cluster Headache ,Migraine Disorders ,Neurology & Neurosurgery ,Clinical sciences - Published
- 2024
47. Activity-Dependent Stabilization of Nascent Dendritic Spines Requires Nonenzymatic CaMKIIα Function
- Author
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Claiborne, Nicole, Anisimova, Margarita, and Zito, Karen
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Basic Behavioral and Social Science ,Behavioral and Social Science ,Neurological ,Female ,Male ,Mice ,Animals ,Dendritic Spines ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Long-Term Potentiation ,Hippocampus ,RNA ,Small Interfering ,CaMKII ,dendritic spine ,glutamate uncaging ,two-photon imaging ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
The outgrowth and stabilization of nascent dendritic spines are crucial processes underlying learning and memory. Most new spines retract shortly after growth; only a small subset is stabilized and integrated into the new circuit connections that support learning. New spine stabilization has been shown to rely upon activity-dependent molecular mechanisms that also contribute to long-term potentiation (LTP) of synaptic strength. Indeed, disruption of the activity-dependent targeting of the kinase CaMKIIα to the GluN2B subunit of the NMDA-type glutamate receptor disrupts both LTP and activity-dependent stabilization of new spines. Yet it is not known which of CaMKIIα's many enzymatic and structural functions are important for new spine stabilization. Here, we used two-photon imaging and photolysis of caged glutamate to monitor the activity-dependent stabilization of new dendritic spines on hippocampal CA1 neurons from mice of both sexes in conditions where CaMKIIα functional and structural interactions were altered. Surprisingly, we found that inhibiting CaMKIIα kinase activity either genetically or pharmacologically did not impair activity-dependent new spine stabilization. In contrast, shRNA knockdown of CaMKIIα abolished activity-dependent new spine stabilization, which was rescued by co-expressing shRNA-resistant full-length CaMKIIα, but not by a truncated monomeric CaMKIIα. Notably, overexpression of phospho-mimetic CaMKIIα-T286D, which exhibits activity-independent targeting to GluN2B, enhanced basal new spine survivorship in the absence of additional glutamatergic stimulation, even when kinase activity was disrupted. Together, our results support a model in which nascent dendritic spine stabilization requires structural and scaffolding interactions mediated by dodecameric CaMKIIα that are independent of its enzymatic activities.
- Published
- 2024
48. Dissociable Contributions of Basolateral Amygdala and Ventrolateral Orbitofrontal Cortex to Flexible Learning Under Uncertainty
- Author
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Aguirre, CG, Woo, JH, Romero-Sosa, JL, Rivera, ZM, Tejada, AN, Munier, JJ, Perez, J, Goldfarb, M, Das, K, Gomez, M, Ye, T, Pannu, J, Evans, K, O'Neill, PR, Spigelman, I, Soltani, A, and Izquierdo, A
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Basic Behavioral and Social Science ,Drug Abuse (NIDA only) ,Substance Misuse ,Neurosciences ,Behavioral and Social Science ,Rats ,Male ,Female ,Animals ,Uncertainty ,Basolateral Nuclear Complex ,Rats ,Long-Evans ,Prefrontal Cortex ,Reversal Learning ,DREADDs ,action learning ,deterministic ,probabilistic ,reward learning ,stimulus learning ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Reversal learning measures the ability to form flexible associations between choice outcomes with stimuli and actions that precede them. This type of learning is thought to rely on several cortical and subcortical areas, including the highly interconnected orbitofrontal cortex (OFC) and basolateral amygdala (BLA), and is often impaired in various neuropsychiatric and substance use disorders. However, the unique contributions of these regions to stimulus- and action-based reversal learning have not been systematically compared using a chemogenetic approach particularly before and after the first reversal that introduces new uncertainty. Here, we examined the roles of ventrolateral OFC (vlOFC) and BLA during reversal learning. Male and female rats were prepared with inhibitory designer receptors exclusively activated by designer drugs targeting projection neurons in these regions and tested on a series of deterministic and probabilistic reversals during which they learned about stimulus identity or side (left or right) associated with different reward probabilities. Using a counterbalanced within-subject design, we inhibited these regions prior to reversal sessions. We assessed initial and pre-/post-reversal changes in performance to measure learning and adjustments to reversals, respectively. We found that inhibition of the ventrolateral orbitofrontal cortex (vlOFC), but not BLA, eliminated adjustments to stimulus-based reversals. Inhibition of BLA, but not vlOFC, selectively impaired action-based probabilistic reversal learning, leaving deterministic reversal learning intact. vlOFC exhibited a sex-dependent role in early adjustment to action-based reversals, but not in overall learning. These results reveal dissociable roles for BLA and vlOFC in flexible learning and highlight a more crucial role for BLA in learning meaningful changes in the reward environment.
- Published
- 2024
49. Brain energy metabolism: A roadmap for future research
- Author
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Rae, Caroline D, Baur, Joseph A, Borges, Karin, Dienel, Gerald, Díaz‐García, Carlos Manlio, Douglass, Starlette R, Drew, Kelly, Duarte, João MN, Duran, Jordi, Kann, Oliver, Kristian, Tibor, Lee‐Liu, Dasfne, Lindquist, Britta E, McNay, Ewan C, Robinson, Michael B, Rothman, Douglas L, Rowlands, Benjamin D, Ryan, Timothy A, Scafidi, Joseph, Scafidi, Susanna, Shuttleworth, C William, Swanson, Raymond A, Uruk, Gökhan, Vardjan, Nina, Zorec, Robert, and McKenna, Mary C
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Neurosciences ,Nutrition ,Rare Diseases ,Brain Disorders ,Underpinning research ,1.1 Normal biological development and functioning ,Neurological ,GLUT4 ,acetate ,aerobic glycolysis ,insulin ,noradrenaline ,Neurology & Neurosurgery ,Biochemistry and cell biology - Abstract
Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+ , as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.
- Published
- 2024
50. Rapid fluctuations in functional connectivity of cortical networks encode spontaneous behavior
- Author
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Benisty, Hadas, Barson, Daniel, Moberly, Andrew H, Lohani, Sweyta, Tang, Lan, Coifman, Ronald R, Crair, Michael C, Mishne, Gal, Cardin, Jessica A, and Higley, Michael J
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Behavioral and Social Science ,Bioengineering ,Basic Behavioral and Social Science ,Mental Health ,1.1 Normal biological development and functioning ,Neurological ,Mice ,Animals ,Neurons ,Magnetic Resonance Imaging ,Wakefulness ,Neocortex ,Brain Mapping ,Neural Pathways ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Experimental work across species has demonstrated that spontaneously generated behaviors are robustly coupled to variations in neural activity within the cerebral cortex. Functional magnetic resonance imaging data suggest that temporal correlations in cortical networks vary across distinct behavioral states, providing for the dynamic reorganization of patterned activity. However, these data generally lack the temporal resolution to establish links between cortical signals and the continuously varying fluctuations in spontaneous behavior observed in awake animals. Here, we used wide-field mesoscopic calcium imaging to monitor cortical dynamics in awake mice and developed an approach to quantify rapidly time-varying functional connectivity. We show that spontaneous behaviors are represented by fast changes in both the magnitude and correlational structure of cortical network activity. Combining mesoscopic imaging with simultaneous cellular-resolution two-photon microscopy demonstrated that correlations among neighboring neurons and between local and large-scale networks also encode behavior. Finally, the dynamic functional connectivity of mesoscale signals revealed subnetworks not predicted by traditional anatomical atlas-based parcellation of the cortex. These results provide new insights into how behavioral information is represented across the neocortex and demonstrate an analytical framework for investigating time-varying functional connectivity in neural networks.
- Published
- 2024
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