Progressive loss of motor neurons is the hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain incompletely understood. In this study, we investigate the effects of C21ORF2 mutations, a gene recently linked to ALS, and find that primary cilia are dysfunctional. Human patient-derived mutant C21ORF2 motor neurons have a reduced ciliary

In this Journal Club, Michaela Fencková discusses a study published in 2020 that examined the effects of acute systemic inflammation on brain glucose metabolism in the context of delirium.

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic

A population of macrophages has been found in muscle spindles that release glutamate, activate primary sensory afferents that are part of the stretch reflex, and have a role in regulating locomotion.

Heart failure (HF) is associated with progressive reduction in cerebral blood flow (CBF) and neurodegenerative changes leading to cognitive decline. The glymphatic system is crucial for the brain's waste removal, and its dysfunction is linked to neurodegeneration. In this study, we used a mouse model of HF, induced by myocardial infarction (MI), to investigate the effects of HF with reduced ejection

Evidence from neuropathological cohorts indicates that a CSF α-synuclein (α-syn) seed amplification assay (SAA) may provide quantitative kinetic parameters correlating with α-syn pathology burden in patients with Lewy body disease (LBD). Studies are needed to assess their longitudinal trend during the pre-symptomatic and clinical disease phases and their correlation with measures of disease progression

Correction to: Nature Neuroscience https://doi.org/10.1038/s41593-024-01806-0, published online 3 December 2024.

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. We have identified in the largest-assembled CV cohort (>2,697 parent-proband trios) an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15). Eight unrelated patients with ventriculomegaly

Plasma phosphorylated-tau217 (p-tau217) has been shown to be one of the most accurate diagnostic markers for Alzheimer’s disease. No studies have compared the clinical performance of p-tau217 as assessed by the fully automated Lumipulse and single molecule array (SIMOA) AlZpath p-tau217. The study included 392 participants, 162 with Alzheimer’s disease, 70 with other neurodegenerative diseases with

Correction to: Nature Neuroscience https://doi.org/10.1038/s41593-022-01022-8, published online 8 Marcxh 2022.

Hostility often co-occurs in parents and associates with increased aggression and inattention problems in children. In this population-based cohort of 484 mother–father–child neuroimaging trios, we investigated the degree to which associations of prenatal and childhood parental hostility would be associated with maternal, paternal, and child brain structural differences. Also, we examined whether hippocampal

Impairments in synaptic dynamics and stability are observed both in neurodegenerative disorders and in the healthy aging cortex, which exhibits elevated dendritic spine turnover and decreased long-term stability of excitatory connections at baseline, as well as an altered response to plasticity induction. In addition to the discrete gain and loss of synapses, spines also change in size and strength

Barn owls enable investigation of neural mechanisms underlying stimulus selection of concurrent stimuli. The audiovisual space map in the optic tectum (OT), avian homolog of the superior colliculus, encodes relative strength of concurrent auditory stimuli through spike response rate and interneuronal spike train synchrony (STS). Open questions remain regarding stimulus selection in downstream forebrain

Cognitive control is engaged by working memory processes and high-demand situations like antisaccade, where one must suppress a prepotent response. While it is known to be supported by the frontoparietal control network, how intra- and interareal dynamics contribute to cognitive control processes remains unclear. N-Methyl-d-aspartate glutamate receptors (NMDARs) play a key role in prefrontal dynamics

Mutations in human VPS4A are associated with neurodevelopmental defects, including motor delays and defective muscle tone. VPS4A encodes a AAA-ATPase required for membrane scission, but how mutations in VPS4A lead to impaired control of motor function is not known. Here we identified a mutation in zebrafish vps4a, T248I, that affects sensorimotor transformation. Biochemical analyses indicate that the

While previous works established the inhibitory role of alpha oscillations during working memory maintenance, it remains an open question whether such an inhibitory control is a top-down process. Here, we attempted to disentangle this issue by considering the spatiotemporal component of waves in the alpha band, i.e., alpha traveling waves. We reanalyzed two pre-existing and open-access EEG datasets

Protocadherins, a family of adhesion molecules with a crucial role in cell–cell interactions, have emerged as key players in neurodevelopmental and psychiatric disorders. In particular, growing evidence links genetic alterations in the protocadherin 9 (PCDH9) gene with autism spectrum disorder and major depressive disorder. Furthermore, Pcdh9 deletion induces neuronal defects in the mouse somatosensory

NMDA receptor (NMDAR)-mediated calcium influx triggers the induction and initial expression of long-term potentiation (LTP). Here we report that in male rodents, ion flux-independent (metabotropic) NMDAR signaling is critical for a third step in the production of enduring LTP, i.e., cytoskeletal changes that stabilize the activity-induced synaptic modifications. Surprisingly, females rely upon estrogen

Huntington's disease (HD) is a progressive neurodegenerative disorder with no cure, characterized by significant neurodegeneration of striatal GABAergic medium spiny neurons (MSNs). Early stages of the disease are characterized by the loss of dopamine 2 receptor–expressing MSNs (D2 MSNs) followed by degeneration of dopamine 1 receptor–expressing MSNs (D1 MSNs), leading to aberrant basal ganglia signaling

Interhemispheric anatomical differences have long been thought to be related to language lateralization. Previous studies have explored whether asymmetries in the diffusion characteristics of white matter language tracts are consistent with language lateralization. These studies, typically with smaller cohorts, yielded mixed results. This study investigated whether connectomic analysis of quantitative

Layer 4 of rabbit V1 contains fast-spiking GABAergic interneurons (suspected inhibitory interneurons, SINs) that receive potent synaptic input from the LGN and generate fast, local feed-forward inhibition. These cells display receptive fields with overlapping ON/OFF subregions, non-linear spatial summation, very broad orientation/directional tuning, and high spontaneous and visually-driven firing rates

Working memory updating is an important executive process. Here, we study the single-neuron mechanisms involved in updating versus protecting memory from distractors in the macaque prefrontal cortex. We recorded single-neuron activity from the lateral prefrontal cortex (LPFC) and prearcuate cortex (PAC) while male monkeys performed a task that required them to update their memory of target locations

Cerebral small vessel disease (cSVD) causes lacunar stroke (LS), intracerebral haemorrhage, and is the most common pathology underlying vascular dementia. However, there are few trials examining whether treating conventional cardiovascular risk factors reduce stroke risk in cSVD, as opposed to stroke as a whole. We used Mendelian randomization techniques to investigate which risk factors are causally

Concurrent neurodegenerative and vascular pathologies pose a diagnostic challenge in the clinical setting, with histopathology remaining the definitive modality for dementia-type diagnosis. To address this clinical challenge, we introduce a neuropathology-based, data-driven, multi-label deep learning framework to identify and quantify in-vivo biomarkers for Alzheimer's disease (AD), vascular dementia

The mammalian auditory system encodes sounds with subtypes of spiral ganglion neurons (SGNs) that differ in sound level sensitivity, permitting discrimination across a wide range of levels. Recent work suggests the physiologically-defined SGN subtypes correspond to at least three molecular subtypes. It is not known how information from the different subtypes converges within the cochlear nucleus. We

Spiral ganglion neuron (SGN) degeneration is a candidate factor for reduced hearing outcomes in cochlear implant (CI) users. However, there is no procedure available to identify CI contacts close to focal SGN degeneration in human patients. In an animal model, we assessed the impact of focal SGN degeneration on electrical responsiveness and derived an electrophysiological marker for the presence, location

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) often requires prolonged ongoing treatment to prevent worsening. The efficacy of rituximab in preventing worsening after the discontinuation of immunoglobulin therapy in CIDP patients was assessed. In this randomized, double-blind, placebo-controlled study, conducted at seven Italian hospitals, CIDP patients under immunoglobulin therapy

There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on Phase 2 data, which then fail in Phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression

Genome-wide association studies (GWAS) have increased our understanding of Parkinson’s disease (PD) genetics by identifying common disease-associated variants. However, much of the heritability remains unaccounted for and we hypothesized that this could be partly explained by epistasis, the statistical interaction between two or more genetic variants. Here, we developed a genome-wide non-exhaustive

Over the past two decades there has been increased interest in orphan drug development for rare diseases. However, hurdles to clinical trial design for these disorders remain. This phase 1a/1b study addressed several challenges, while evaluating the safety and tolerability of the novel oral molecule KL1333 in healthy volunteers and subjects with primary mitochondrial disease. KL1333 aims to normalize

The leptomeninges play a pivotal role in the central nervous system (CNS), serving both as a barrier and as a conduit for fluid and cellular transport. Despite their critical functions, our understanding of leptomeningeal development and maturation during human embryogenesis remains limited. This study seeks to bridge this gap. We conducted single-nucleus RNA sequencing on leptomeningeal tissues from

Secondary motor cortical regions, such as the supplementary motor area (SMA) are involved in planning and learning motor sequences, however the neurophysiological mechanisms across these secondary cortical networks remain poorly understood. In primary motor cortex, changes in excitatory and inhibitory neurotransmission (E:I balance) accompany motor sequence learning. In particular, there is an early

The subiculum represents a crucial brain pivot in regulating seizure generalization in temporal lobe epilepsy (TLE), primarily through synergy of local GABAergic and long-projecting glutamatergic signaling. However, little is known about how subicular GABAergic interneurons are involved in a cell-type-specific way. Here, employing Ca2+ fiber photometry, retrograde monosynaptic viral tracing and chemogenetics

Alterations in mitochondrial function are the linchpin in numerous disease states including in the development of chemotherapy-induced neuropathic pain (CIPN), a major dose-limiting toxicity of widely used chemotherapeutic cytotoxins. In CIPN, mitochondrial dysfunction is characterized by deficits in mitochondrial bioenergetics (e.g., decreased ATP production) that are thought to drive the degeneration

Correction to: Nature Neuroscience https://doi.org/10.1038/s41593-021-00908-3, published online 26 August 2021.

The cortex immediately surrounding a brain ischemic lesion, the peri-infarct cortex (PIC), harbors a large part of the potential to recover lost functions. However, our understanding of the neurophysiological conditions in which synaptic plasticity operates remains limited. Here we hypothesized that the chronic imbalance between excitation and inhibition of the PIC prevents the normalization of the

Single-photon optogenetics enables precise, cell-type–specific modulation of neuronal circuits, making it a crucial tool in neuroscience. Its miniaturization in the form of fully implantable wide-field stimulator arrays enables long-term interrogation of cortical circuits and bears promise for brain–machine interfaces for sensory and motor function restoration. However, achieving selective activation

In a real-world environment, the brain must integrate information from multiple sensory modalities, including the auditory and olfactory systems. However, little is known about the neuronal circuits governing how odors influence and modulate sound processing. Here, we investigated the mechanisms underlying auditory–olfactory integration using anatomical, electrophysiological, and optogenetic approaches

Mutations in SYNGAP1, a protein enriched at glutamatergic synapses, cause intellectual disability associated with epilepsy, autism spectrum disorder, and sensory dysfunctions. Several studies showed that Syngap1 regulates the time course of forebrain glutamatergic synapse maturation; however, the developmental role of Syngap1 in inhibitory GABAergic neurons is less clear. GABAergic neurons can be classified

Animal vocalizations and human speech are typically characterized by a complex spectrotemporal structure, composed of multiple harmonics, and patterned as temporally organized sequences. However, auditory research often employed simple artificial acoustic stimuli or their combinations. Here we addressed the question of whether the neuronal responses to natural echolocation call sequences can be predicted