Background and ObjectivesLittle is known about the clinical presentation in patients with comorbid Alzheimer disease neuropathologic change (ADNC) and frontotemporal lobar degeneration (FTLD) neuropathology, despite frequent comorbidity of…
Category: neuroscience
Hypoxia-inducible protein 2 mediates metabolic adaptation of Ly6ChighLy6Glow monocytes after stroke
New study from Weijie Chen, Xin Wang, Tingting Huang, Weifeng Yu.
Florent Ginhoux, Peiying Li (Shanghai Jiao Tong University) and colleagues identifies hypoxia-inducible protein 2 (HIG2) as a key regulator of anti-inflammatory property of Ly6ChighLy6Glow monocyte-derived macrophages in the ischemic brain after stroke through mediating phosphatidylcholine synthesis.
This study identifies hypoxia-inducible protein 2 (HIG2) as a key regulator of anti-inflammatory property of Ly6ChighLy6Glow monocyte-derived macrophages i.
A neuron pair in fruit flies that makes life or death decisions
For the fruit fly, a sense of taste is critical to whether it thrives or dies. The little winged creature has taste organs in its mouthpiece as well as throughout its body, including its legs, abdomen and wing margins. When a fruit fly lands on a ripe or rotting fruit, it instantly receives information about whether the fruit is bitter or sweet. Sweetness indicates a caloric payday that cues the fly to feed; bitterness prompts the fly to move on from the potentially toxic substance.
Researchers in the lab of Brown University professor Gilad Barnea have identified the pair of neurons that make this critical choice. The insights on how flies navigate this complex decision-making process, a process not previously clear to scientists, are published online in Nature Communications.
“If a fly makes just one mistake about what to eat, it may die,” said Barnea, a professor of neuroscience and director of the Center for the Neurobiology of Cells and Circuits at Brown’s Carney Institute for Brain Science. “So the decision is super important. This newly discovered mechanism illustrates the impressive level of computation that a single neuron can do.”
Abstract: Decoding neurodegeneration one cell at a time
https://doi.org/10.1172/JCI199841 As part of the JCI’s Review Series on Neurodegeneration, Olivia Gautier, Thao P. Nguyen & Aaron D. Gitler explore the molecular basis for selective neuronal vulnerability and degeneration and summarize recent advances and applications of single-cell genomic approaches.
How do we decide whether we should choose single-cell or single-nucleus sequencing? This depends on sample types and biological applications. Single-cell sequencing is typically applied to fresh, readily dissociable tissues or cultured cells to study intact cell populations. Because it captures both cytoplasmic and nuclear transcripts, scRNA-seq provides a comprehensive view of cellular gene expression. However, tissue dissociation can induce stress-related transcriptional artifacts and introduce substantial cell-type bias. Large or fragile neurons are often lost during dissociation, whereas smaller cell types, such as astrocytes and oligodendrocytes, tend to be overrepresented. In contrast, single-nucleus sequencing is commonly used for frozen samples or for tissues that are difficult to dissociate, including the brain and spinal cord. Although fresh or fresh-frozen samples are typically used, snRNA-seq is compatible with formalin-fixed, paraffin-embedded (FFPE) samples, enabling the analysis of archived human specimens. A key limitation is that snRNA-seq does not capture cytoplasmic transcripts and is therefore biased toward nuclear, often premature, mRNA species.
Spatial transcriptomics does not require tissue dissociation and enables examination of cellular transcriptomes within their native tissue niches. Some spatial transcriptomic technologies are now compatible with FFPE samples, allowing analyses of preserved clinical specimens along with fixed-frozen and fresh-frozen samples. These technologies can be broadly classified into two main categories: imaging-based and sequencing-based (Figure 2B). Imaging-based approaches, like multiplexed error-robust fluorescence in situ hybridization (MERFISH), spatially resolved transcript amplicon readout mapping (STARmap), and 10x Genomics Xenium, rely on probe hybridization and multiplexed imaging to detect and visualize transcripts at high spatial resolution, often achieving single-cell or even subcellular resolution (17, 18). Although whole-transcriptome measurements are possible, MERFISH typically targets predefined gene panels due to the constraints of iterative hybridization and imaging. In contrast, sequencing-based approaches, including NanoString GeoMx and 10x Genomics Visium, capture RNA on spatially barcoded tissue slides or nanobeads followed by next-generation sequencing. These methods generally recover a broader range of transcripts than imaging-based approaches but, in most cases, do not yet achieve true single-cell resolution. Instead, they measure gene expression within spatial “spots” that encompass multiple cells and therefore rely on computational deconvolution to infer cell-type composition. Newer spatial transcriptomic methods, like spatial enhanced resolution omics sequencing (Stereo-seq) and reverse-padlock amplicon-encoding fluorescence in situ hybridization (RAEFISH), are approaching single-cell and single-molecule resolution (19 – 21).
In this Review, we summarize recent advances and applications of single-cell genomics approaches to study neurodegenerative disorders, including Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington disease (HD). We focus on how these approaches provide insight into the unique vulnerabilities of specific neuronal populations, define novel disease-associated cellular states, and reveal contributions of non-neuronal cells to disease pathogenesis. We then look to the future, envisioning how these technologies will empower genetic screens to uncover modifiers of neurodegeneration and new therapeutic targets.
Precision radio waves may help counter brain diseases
A study has found that precise application of radio waves can change the activity of brain cells in ways that could counter neurological conditions. Led by researchers at NYU Langone Health, the work introduces a technique called transcranial radio frequency stimulation (TRFS), which promises to treat neurological diseases with neither the invasiveness of surgery nor the frequent failure of drugs as patients (e.g., 30% of people with depression and epilepsy) develop resistance.
Published online recently in the journal Brain Stimulation, the study describes the use of radio frequency (RF) energy, which is effective at penetrating biological tissue. The study says TRFS could overcome the limits of older technologies because it can, depending on the nature of the disease, target either a small part of the brain or the entire organ, and it can dial nerve signaling up or down.
“Our study is the first to demonstrate in live mice the potential of the technology to be highly effective for adjusting neural activity,” said senior study author György Buzsáki, MD, Ph.D., the Biggs Professor of Neuroscience in the Department of Neuroscience at NYU Grossman School of Medicine. “The need for better, noninvasive techniques is becoming ever more urgent, with one in three people globally affected by some form of brain disorder during their lifetime,” said Dr. Buzsáki, also faculty at the Institute for Translational Neuroscience.
Study maps gene activity linked to neurotransmission in living brains
Researchers have identified a distinct and reproducible gene expression program associated with neurotransmission in the living human brain, offering unprecedented insight into the molecular mechanisms that support human cognition, emotion, and behavior. The findings were published February 19 in Molecular Psychiatry.
Neurotransmission-the electrical and chemical signaling between neurons-is fundamental to all brain function. Until now, most gene expression studies of the human brain have relied on postmortem tissue, limiting scientists’ ability to understand which genes are actively involved in real-time neuronal communication.
In this study, investigators integrated gene expression profiling from the prefrontal cortex with direct intracranial measures of neurotransmission collected from the brains of more than 100 individuals as they underwent neurosurgical procedures. By combining molecular data with real-time physiological recordings, the team identified a coordinated set of genes whose activity tracks with neuronal signaling-a transcriptional program associated with neurotransmission.
FOXJ3 gene variants linked to drug-resistant focal epilepsy
Researchers have discovered that mutations in the FOXJ3 gene act as a “master switch” failure, disrupting how the brain builds its layers and leading to FCD, a primary cause of drug-resistant epilepsy. The study reveals how FOXJ3 controls the formation of brain cortical layers during brain development by regulating the PTEN–mTOR signaling pathway.
The PTEN-mTOR signaling pathway acts as a critical control system for cell growth, proliferation, metabolism, and survival. When this system malfunctions, it causes many neurological disorders including FCD, tuberous sclerosis complex and neurofibromatosis. The discovery of FOXJ3, a transcription factor (a protein that regulates gene activity), as a new cause of these “mTOR pathway diseases” (mTORpathies) provides new insight into the biological origins of epilepsy and cortical malformations, as well as potential new treatments.
The research team by studying families with inherited focal epilepsy alongside mouse and single-cell analysis, uncovered how FOXJ3 mutations disrupt how brain cells move to their correct locations and take on their proper roles during early brain development.
“Focal cortical dysplasia is one of the most common causes of epilepsy that does not respond to medication, yet in many patients the underlying cause remains unknown,” said the corresponding author. “Our findings identify FOXJ3 as the critical genetic and molecular link between abnormal brain development and epilepsy.” ScienceMission sciencenewshighlights.
