journal
https://read.qxmd.com/read/36948206/neuronal-identity-defines-%C3%AE-synuclein-and-tau-toxicity
#1
JOURNAL ARTICLE
Roman Praschberger, Sabine Kuenen, Nils Schoovaerts, Natalie Kaempf, Jeevanjot Singh, Jasper Janssens, Jef Swerts, Eliana Nachman, Carles Calatayud, Stein Aerts, Suresh Poovathingal, Patrik Verstreken
Pathogenic α-synuclein and tau are critical drivers of neurodegeneration, and their mutations cause neuronal loss in patients. Whether the underlying preferential neuronal vulnerability is a cell-type-intrinsic property or a consequence of increased expression levels remains elusive. Here, we explore cell-type-specific α-synuclein and tau expression in human brain datasets and use deep phenotyping as well as brain-wide single-cell RNA sequencing of >200 live neuron types in fruit flies to determine which cellular environments react most to α-synuclein or tau toxicity...
March 13, 2023: Neuron
https://read.qxmd.com/read/36931278/downregulation-of-hsp90-and-the-antimicrobial-peptide-mtk-suppresses-poly-gr-induced-neurotoxicity-in-c9orf72-als-ftd
#2
JOURNAL ARTICLE
Soojin Lee, Yong-Woo Jun, Gabriel R Linares, Brandon Butler, Yeliz Yuva-Adyemir, Jill Moore, Gopinath Krishnan, Bryan Ruiz-Juarez, Manuel Santana, Marine Pons, Neal Silverman, Zhiping Weng, Justin K Ichida, Fen-Biao Gao
GGGGCC repeat expansion in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat RNAs can be translated into dipeptide repeat proteins, including poly(GR), whose mechanisms of action remain largely unknown. In an RNA-seq analysis of poly(GR) toxicity in Drosophila, we found that several antimicrobial peptide genes, such as metchnikowin (Mtk), and heat shock protein (Hsp) genes are activated. Mtk knockdown in the fly eye or in all neurons suppresses poly(GR) neurotoxicity...
March 10, 2023: Neuron
https://read.qxmd.com/read/36921603/bistability-of-prefrontal-states-gates-access-to-consciousness
#3
JOURNAL ARTICLE
Abhilash Dwarakanath, Vishal Kapoor, Joachim Werner, Shervin Safavi, Leonid A Fedorov, Nikos K Logothetis, Theofanis I Panagiotaropoulos
Access of sensory information to consciousness has been linked to the ignition of content-specific representations in association cortices. How does ignition interact with intrinsic cortical state fluctuations to give rise to conscious perception? We addressed this question in the prefrontal cortex (PFC) by combining multi-electrode recordings with a binocular rivalry (BR) paradigm inducing spontaneously driven changes in the content of consciousness, inferred from the reflexive optokinetic nystagmus (OKN) pattern...
March 10, 2023: Neuron
https://read.qxmd.com/read/36921602/bilirubin-gates-the-trpm2-channel-as-a-direct-agonist-to-exacerbate-ischemic-brain-damage
#4
JOURNAL ARTICLE
Han-Wei Liu, Li-Na Gong, Ke Lai, Xia-Fei Yu, Zhen-Qi Liu, Ming-Xian Li, Xin-Lu Yin, Min Liang, Hao-Song Shi, Lin-Hua Jiang, Wei Yang, Hai-Bo Shi, Lu-Yang Wang, Shan-Kai Yin
Stroke prognosis is negatively associated with an elevation of serum bilirubin, but how bilirubin worsens outcomes remains mysterious. We report that post-, but not pre-, stroke bilirubin levels among inpatients scale with infarct volume. In mouse models, bilirubin increases neuronal excitability and ischemic infarct, whereas ischemic insults induce the release of endogenous bilirubin, all of which are attenuated by knockout of the TRPM2 channel or its antagonist A23. Independent of canonical TRPM2 intracellular agonists, bilirubin and its metabolic derivatives gate the channel opening, whereas A23 antagonizes it by binding to the same cavity...
March 8, 2023: Neuron
https://read.qxmd.com/read/36917978/ultrasound-as-a-versatile-tool-for-short-and-long-term-improvement-and-monitoring-of-brain-function
#5
REVIEW
Daniel G Blackmore, Daniel Razansky, Jürgen Götz
Treating the brain with focused ultrasound (FUS) at low intensities elicits diverse responses in neurons, astroglia, and the extracellular matrix. In combination with intravenously injected microbubbles, FUS also opens the blood-brain barrier (BBB) and facilitates focal drug delivery. However, an incompletely understood cellular specificity and a wide parameter space currently limit the optimal application of FUS in preclinical and human studies. In this perspective, we discuss how different FUS modalities can be utilized to achieve short- and long-term improvements, thereby potentially treating brain disorders...
March 8, 2023: Neuron
https://read.qxmd.com/read/36924773/an-iterative-neural-processing-sequence-orchestrates-feeding
#6
JOURNAL ARTICLE
Qingqing Liu, Xing Yang, Moxuan Luo, Junying Su, Jinling Zhong, Xiaofen Li, Rosa H M Chan, Liping Wang
Feeding requires sophisticated orchestration of neural processes to satiate appetite in natural, capricious settings. However, the complementary roles of discrete neural populations in orchestrating distinct behaviors and motivations throughout the feeding process are largely unknown. Here, we delineate the behavioral repertoire of mice by developing a machine-learning-assisted behavior tracking system and show that feeding is fragmented and divergent motivations for food consumption or environment exploration compete throughout the feeding process...
March 7, 2023: Neuron
https://read.qxmd.com/read/36924772/genetically-encoded-sensors-for-measuring-histamine-release-both-in%C3%A2-vitro-and-in%C3%A2-vivo
#7
JOURNAL ARTICLE
Hui Dong, Mengyao Li, Yuqi Yan, Tongrui Qian, Yunzhi Lin, Xiaoyuan Ma, Henry F Vischer, Can Liu, Guochuan Li, Huan Wang, Rob Leurs, Yulong Li
Histamine (HA) is a key biogenic monoamine involved in a wide range of physiological and pathological processes in both the central and peripheral nervous systems. Because the ability to directly measure extracellular HA in real time will provide important insights into the functional role of HA in complex circuits under a variety of conditions, we developed a series of genetically encoded G-protein-coupled receptor-activation-based (GRAB) HA (GRABHA ) sensors with good photostability, sub-second kinetics, nanomolar affinity, and high specificity...
March 7, 2023: Neuron
https://read.qxmd.com/read/36917979/propofol-exerts-anti-anhedonia-effects-via-inhibiting-the-dopamine-transporter
#8
JOURNAL ARTICLE
Xiao-Na Zhu, Jie Li, Gao-Lin Qiu, Lin Wang, Chen Lu, Yi-Ge Guo, Ke-Xin Yang, Fang Cai, Tao Xu, Ti-Fei Yuan, Ji Hu
Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia. Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT...
March 6, 2023: Neuron
https://read.qxmd.com/read/36898375/neural-knowledge-assembly-in-humans-and-neural-networks
#9
JOURNAL ARTICLE
Stephanie Nelli, Lukas Braun, Tsvetomira Dumbalska, Andrew Saxe, Christopher Summerfield
Human understanding of the world can change rapidly when new information comes to light, such as when a plot twist occurs in a work of fiction. This flexible "knowledge assembly" requires few-shot reorganization of neural codes for relations among objects and events. However, existing computational theories are largely silent about how this could occur. Here, participants learned a transitive ordering among novel objects within two distinct contexts before exposure to new knowledge that revealed how they were linked...
March 6, 2023: Neuron
https://read.qxmd.com/read/36898374/the-neural-architecture-of-theory-based-reinforcement-learning
#10
JOURNAL ARTICLE
Momchil S Tomov, Pedro A Tsividis, Thomas Pouncy, Joshua B Tenenbaum, Samuel J Gershman
Humans learn internal models of the world that support planning and generalization in complex environments. Yet it remains unclear how such internal models are represented and learned in the brain. We approach this question using theory-based reinforcement learning, a strong form of model-based reinforcement learning in which the model is a kind of intuitive theory. We analyzed fMRI data from human participants learning to play Atari-style games. We found evidence of theory representations in prefrontal cortex and of theory updating in prefrontal cortex, occipital cortex, and fusiform gyrus...
March 6, 2023: Neuron
https://read.qxmd.com/read/36917980/upregulation-of-syngap1-expression-in-mice-and-human-neurons-by-redirecting-alternative-splicing
#11
JOURNAL ARTICLE
Runwei Yang, Xinran Feng, Alejandra Arias-Cavieres, Robin M Mitchell, Ashleigh Polo, Kaining Hu, Rong Zhong, Cai Qi, Rachel S Zhang, Nathaniel Westneat, Cristabel A Portillo, Marcelo A Nobrega, Christian Hansel, Alfredo J Garcia Iii, Xiaochang Zhang
The Ras GTPase-activating protein SYNGAP1 plays a central role in synaptic plasticity, and de novo SYNGAP1 mutations are among the most frequent causes of autism and intellectual disability. How SYNGAP1 is regulated during development and how to treat SYNGAP1-associated haploinsufficiency remain challenging questions. Here, we characterize an alternative 3' splice site (A3SS) of SYNGAP1 that induces nonsense-mediated mRNA decay (A3SS-NMD) in mouse and human neural development. We demonstrate that PTBP1/2 directly bind to and promote SYNGAP1 A3SS inclusion...
March 3, 2023: Neuron
https://read.qxmd.com/read/36917977/gasdermin-e-mediates-mitochondrial-damage-in-axons-and-neurodegeneration
#12
JOURNAL ARTICLE
Dylan V Neel, Himanish Basu, Georgia Gunner, Matthew D Bergstresser, Richard M Giadone, Haeji Chung, Rui Miao, Vicky Chou, Eliza Brody, Xin Jiang, Edward Lee, Michelle E Watts, Christine Marques, Aaron Held, Brian Wainger, Clotilde Lagier-Tourenne, Yong-Jie Zhang, Leonard Petrucelli, Tracey L Young-Pearse, Alice S Chen-Plotkin, Lee L Rubin, Judy Lieberman, Isaac M Chiu
Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction...
March 3, 2023: Neuron
https://read.qxmd.com/read/36889313/communication-dynamics-in-the-human-connectome-shape-the-cortex-wide-propagation-of-direct-electrical-stimulation
#13
JOURNAL ARTICLE
Caio Seguin, Maciej Jedynak, Olivier David, Sina Mansour, Olaf Sporns, Andrew Zalesky
Communication between gray matter regions underpins all facets of brain function. We study inter-areal communication in the human brain using intracranial EEG recordings, acquired following 29,055 single-pulse direct electrical stimulations in a total of 550 individuals across 20 medical centers (average of 87 ± 37 electrode contacts per subject). We found that network communication models-computed on structural connectivity inferred from diffusion MRI-can explain the causal propagation of focal stimuli, measured at millisecond timescales...
March 2, 2023: Neuron
https://read.qxmd.com/read/36893755/choroid-plexus-targeted-nkcc1-overexpression-to-treat-post-hemorrhagic-hydrocephalus
#14
JOURNAL ARTICLE
Cameron Sadegh, Huixin Xu, Jason Sutin, Benoit Fatou, Suhasini Gupta, Aja Pragana, Milo Taylor, Peter N Kalugin, Miriam E Zawadzki, Osama Alturkistani, Frederick B Shipley, Neil Dani, Ryann M Fame, Zainab Wurie, Pratik Talati, Riana L Schleicher, Eric M Klein, Yong Zhang, Michael J Holtzman, Christopher I Moore, Pei-Yi Lin, Aman B Patel, Benjamin C Warf, W Taylor Kimberly, Hanno Steen, Mark L Andermann, Maria K Lehtinen
Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+ ] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation...
March 1, 2023: Neuron
https://read.qxmd.com/read/36893756/glutamatergic-and-gabaergic-neurons-in-pontine-central-gray-mediate-opposing-valence-specific-behaviors-through-a-global-network
#15
JOURNAL ARTICLE
Cuiyu Xiao, Jinxing Wei, Guang-Wei Zhang, Can Tao, Junxiang J Huang, Li Shen, Ian R Wickersham, Huizhong W Tao, Li I Zhang
Extracting the valence of environmental cues is critical for animals' survival. How valence in sensory signals is encoded and transformed to produce distinct behavioral responses remains not well understood. Here, we report that the mouse pontine central gray (PCG) contributes to encoding both negative and positive valences. PCG glutamatergic neurons were activated selectively by aversive, but not reward, stimuli, whereas its GABAergic neurons were preferentially activated by reward signals. The optogenetic activation of these two populations resulted in avoidance and preference behavior, respectively, and was sufficient to induce conditioned place aversion/preference...
February 28, 2023: Neuron
https://read.qxmd.com/read/36889314/transcriptional-control-of-nucleus-accumbens-neuronal-excitability-by-retinoid-x-receptor-alpha-tunes-sensitivity-to-drug-rewards
#16
JOURNAL ARTICLE
Arthur Godino, Marine Salery, Romain Durand-de Cuttoli, Molly S Estill, Leanne M Holt, Rita Futamura, Caleb J Browne, Philipp Mews, Peter J Hamilton, Rachael L Neve, Li Shen, Scott J Russo, Eric J Nestler
The complex nature of the transcriptional networks underlying addictive behaviors suggests intricate cooperation between diverse gene regulation mechanisms that go beyond canonical-activity-dependent pathways. Here, we implicate in this process a nuclear receptor transcription factor, retinoid X receptor alpha (RXRα), which we initially identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that although its own expression remains unaltered after cocaine exposure, RXRα controls plasticity- and addiction-relevant transcriptional programs in both dopamine receptor D1- and D2-expressing medium spiny neurons, which in turn modulate intrinsic excitability and synaptic activity of these NAc cell types...
February 28, 2023: Neuron
https://read.qxmd.com/read/36868221/molecular-and-cellular-mechanisms-of-the-first-social-relationship-a-conserved-role-of-5-ht-from-mice-to-monkeys-upstream-of-oxytocin
#17
JOURNAL ARTICLE
Yan Liu, Liang Shan, Tiane Liu, Juan Li, Yongchang Chen, Changhong Sun, Chaojuan Yang, Xiling Bian, Yuyu Niu, Chen Zhang, Jianzhong Xi, Yi Rao
Maternal affiliation by infants is the first social behavior of mammalian animals. We report here that elimination of the Tph2 gene essential for serotonin synthesis in the brain reduced affiliation in mice, rats, and monkeys. Calcium imaging and c-fos immunostaining showed maternal odors activation of serotonergic neurons in the raphe nuclei (RNs) and oxytocinergic neurons in the paraventricular nucleus (PVN). Genetic elimination of oxytocin (OXT) or its receptor reduced maternal preference. OXT rescued maternal preference in mouse and monkey infants lacking serotonin...
February 25, 2023: Neuron
https://read.qxmd.com/read/36863345/a-spinal-muscular-atrophy-modifier-implicates-the-smn-protein-in-snare-complex-assembly-at-neuromuscular-synapses
#18
JOURNAL ARTICLE
Jeong-Ki Kim, Narendra N Jha, Tomoyuki Awano, Charlotte Caine, Kishore Gollapalli, Emily Welby, Seung-Soo Kim, Andrea Fuentes-Moliz, Xueyong Wang, Zhihua Feng, Fusako Sera, Taishi Takeda, Shunichi Homma, Chien-Ping Ko, Lucia Tabares, Allison D Ebert, Mark M Rich, Umrao R Monani
Reduced survival motor neuron (SMN) protein triggers the motor neuron disease, spinal muscular atrophy (SMA). Restoring SMN prevents disease, but it is not known how neuromuscular function is preserved. We used model mice to map and identify an Hspa8G470R synaptic chaperone variant, which suppressed SMA. Expression of the variant in the severely affected mutant mice increased lifespan >10-fold, improved motor performance, and mitigated neuromuscular pathology. Mechanistically, Hspa8G470R altered SMN2 splicing and simultaneously stimulated formation of a tripartite chaperone complex, critical for synaptic homeostasis, by augmenting its interaction with other complex members...
February 22, 2023: Neuron
https://read.qxmd.com/read/36841241/hidden-behavioral-fingerprints-in-epilepsy
#19
JOURNAL ARTICLE
Tilo Gschwind, Ayman Zeine, Ivan Raikov, Jeffrey E Markowitz, Winthrop F Gillis, Sylwia Felong, Lori L Isom, Sandeep Robert Datta, Ivan Soltesz
Epilepsy is a major disorder affecting millions of people. Although modern electrophysiological and imaging approaches provide high-resolution access to the multi-scale brain circuit malfunctions in epilepsy, our understanding of how behavior changes with epilepsy has remained rudimentary. As a result, screening for new therapies for children and adults with devastating epilepsies still relies on the inherently subjective, semi-quantitative assessment of a handful of pre-selected behavioral signs of epilepsy in animal models...
February 17, 2023: Neuron
https://read.qxmd.com/read/36822200/dna-initiated-epigenetic-cascades-driven-by-c9orf72-hexanucleotide-repeat
#20
JOURNAL ARTICLE
Yang Liu, Zhiyuan Huang, Honghe Liu, Zhicheng Ji, Amit Arora, Danfeng Cai, Hongjin Wang, Mingming Liu, Eric A J Simko, Yanjun Zhang, Goran Periz, Zhe Liu, Jiou Wang
The C9orf72 hexanucleotide repeat expansion (HRE) is the most frequent genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we describe the pathogenic cascades that are initiated by the C9orf72 HRE DNA. The HRE DNA binds to its protein partner DAXX and promotes its liquid-liquid phase separation, which is capable of reorganizing genomic structures. An HRE-dependent nuclear accumulation of DAXX drives chromatin remodeling and epigenetic changes such as histone hypermethylation and hypoacetylation in patient cells...
February 17, 2023: Neuron
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