Spontaneous glutamate release activates mGluR signaling to drive rapid antidepressant responses.

Major depressive disorder affects millions worldwide, yet current treatments require prolonged administration. In contrast, ketamine produces rapid antidepressant effects by blocking spontaneous N-Methyl-D-Aspartate (NMDA) receptor signaling, which lifts the suppression of protein synthesis and triggers homeostatic synaptic plasticity. Here, we identify a parallel signaling pathway involving metabotropic glutamate receptor 5 (mGluR5) that promotes rapid antidepressant-like effects.

Spatial profiling of longitudinal glioblastoma reveals consistent changes in cellular architecture, post-treatment.

Background: Glioblastoma (GBM), the most aggressive adult brain cancer, comprises a complex tumour microenvironment (TME) with diverse cellular interactions that drive progression and pathobiology. The aim of this study was to understand how these spatial patterns and interactions evolve with treatment.

Methods: To explore these relationships, we employed imaging mass cytometry to measure the expression of 34 protein markers, enabling the identification of GBM-specific cell types and their interactions at single-cell protein level in paired primary (pre-treatment) and recurrent (post-treatment) GBM samples from five patients.

Distinct Electrophysiological Signatures Define Neuronal Subtypes in the Fasciola Cinereum.

The fasciola cinereum (FC) is a small, conserved hippocampal subregion whose function has remained largely unexplored. Anatomically situated between dorsal CA1 and the third ventricle in rodents, the FC receives diverse cortical and subcortical inputs yet is often omitted from hippocampal circuit models. There remains a fundamental knowledge gap regarding the cell types and intrinsic properties of neurons in FC and whether they are distinct from neighboring hippocampal subregions.

Effects of DNA methylation inhibitors on light-induced circadian clock plasticity.

The suprachiasmatic nucleus (SCN) of the hypothalamus is a principal light-responsive circadian clock that adjusts circadian rhythms in mammalian physiology and behavior to changes in external light signals. Although mechanisms underlying how light acutely resets the timing of circadian rhythms have been characterized, it remains elusive how light signals induce lasting changes in circadian period, known as period after-effects. Here we have found that the period after-effects on circadian behavior of changing photoperiods are blocked by application of the DNA methyltransferase inhibitor RG108 near the SCN.

Protocol for Disome-seq to identify transcriptome-wide ribosome collisions in yeast cells.

When translation elongation is hindered, stalled ribosomes can collide with trailing ribosomes and form ribosome collision complexes also known as disomes. Disomes are sensed in the cell to trigger signaling events, and therefore it is important to determine their frequency and distribution across transcripts. Here, we provide the protocol for Disome-seq in Saccharomyces cerevisiae (yeast) cells to enable transcriptome-wide detection of disomes.

Recommendations for Increasing Sample Diversity in Autism Research: Lessons from Multisensory Studies.

In 2024, the United States House of Representatives passed ruling H.R.7213, the Autism CARES Act, which, if passed by the Senate, will reauthorize funding to extant national autism research programs, with an emphasis on including autistic individuals significantly affected by the disorder.

Proteostasis and Unfolded Protein Response Dynamics in Human Neuron and Mouse Glia Co-culture Reveal Cell-Specific Aging Responses.

Proteostasis, or protein homeostasis, is a tightly regulated network of cellular pathways essential for maintaining proper protein folding, trafficking, and degradation. Neurons are particularly vulnerable to proteostasis collapse due to their post-mitotic and long-lived nature and thus represent a unique cell type to understand the dynamics of proteostasis throughout development, maturation, and aging. Here, we utilized a dual-species co-culture model of human excitatory neurons and mouse glia to investigate cell type-specific, age-related changes in the proteostasis network using data-independent acquisition (DIA) LC-MS/MS proteomics.

Experience reorganizes content-specific memory traces in macaques.

Memory formation relies on the reorganization of neural activity patterns during experience that persist in subsequent sleep. How these processes promote learning while preserving established memories remains unclear. We recorded neural ensemble activity from hippocampal and associated regions in freely moving macaques as they recalled item sequences presented that day ("new"), one day prior ("recent"), or over two weeks prior ("old").

Development of the arcuate fasciculus is linked to learning gains in reading.

Past studies leveraging cross-sectional data have raised questions surrounding the relationship between diffusion properties of the white matter and academic skills. Some studies have suggested that white matter properties serve as static predictors of academic skills, whereas other studies have observed no such relationship. However, longitudinal studies have suggested that within-individual changes in the white matter are linked to learning gains over time.

Global effects in fMRI reveal brain markers of state and trait anxiety.

Background: To personalize the diagnosis and treatment of anxiety, there is a need to identify biological constructs that underlie self-reported symptoms. Notably, physiological responses and altered levels of arousal are constituents of anxiety and have widespread ("global") effects on fMRI signals across the brain. Therefore, fMRI signatures of global cortical arousal and autonomic physiological responses may provide valuable neuroimaging biomarkers of anxiety.

The atypical adhesion GPCR ADGRA1 controls hippocampal inhibitory circuit function.

Neural circuits contain a diverse array of inhibitory interneurons that control information processing. The cell surface receptors and signaling pathways that modulate cell type specific inhibitory synaptic function are unclear. Here, we identify the atypical adhesion GPCR ADGRA1 as essential for hippocampal PV and SST inhibitory synaptic function.

Glia-derived noncanonical fatty acid binding protein modulates brain lipid storage and clearance.

Glia-derived secretory factors are essential for brain development, physiology, and homeostasis, with their dysfunction linked to a variety of neurological disorders. Through genetic and biochemical approaches, we identified odorant binding protein 44a (Obp44a), a noncanonical α-helical fatty acid binding protein (FABP) highly expressed in central nervous system glia. Obp44a binds long-chain fatty acids and shuttles between glia and neurons, acting as a secretory lipid chaperone and scavenger to support lipid storage, efflux, and redox homeostasis.

Associations Between Audiovisual Integration and Reading Comprehension in Autistic and Non-autistic School-Aged Children.

Although not considered a core feature of autism, autistic children often present with difficulties in reading comprehension, which is a multisensory process involving translation of print to speech sounds (i.e., decoding) and interpreting words in context (i.

The Influence of Schwann Cell Metabolism and Dysfunction on Axon Maintenance.

Schwann cells are the glial cells in the peripheral nervous system responsible for the production of myelin, which is essential for rapid, saltatory conduction in nerves. However, it has become increasingly recognized that Schwann cells are also key regulators of neuron viability and function, especially for sensory neurons. Neurons and Schwann cells form a tightknit, interdependent couple with complex mechanisms of communication that are only beginning to be understood.

Single Cell Profiling in the Sox10 Hirschsprung Mouse Implicates Hox Genes in Enteric Neuron Trajectory Allocation.

Background & Aims: Enteric nervous system (ENS) development requires migration, proliferation, and differentiation of progenitors for normal gastrointestinal (GI) motility. Sox10 deficit causes aganglionosis, modeling Hirschsprung disease (HSCR), and disrupts ratios of postnatal enteric neurons in proximal ganglionated bowel. How Sox10 deficiency alters enteric neuron ratios is unclear.

Preoptic area influences sleep-related seizures in a genetic epilepsy mouse model.

In patients with refractory epilepsy, states of sleep and wakefulness affect the expression of seizures. However, the mechanism by which subcortical sleep circuitry affects seizures is unknown. Here, using Gabrg2Q390X knock-in (KI) genetic epileptic mouse model, we found that during sleep, subcortical preoptic area (POA) neurons were active in het Gabrg2Q390X KI mice and their activity preceded or/and coincided with epileptic (poly)spike-wave discharges.

Profiling the Impact of mGlu/Elfn1 Protein Interactions on the Pharmacology of mGlu Allosteric Modulators.

The group III metabotropic glutamate receptors (mGlu receptors) are predominantly expressed presynaptically throughout the central nervous system (CNS) where they regulate the release of glutamate and GABA. These receptors have recently been shown to be anchored by transsynaptic expression of the laminin proteins ELFN1 and ELFN2. In particular, the mGlu receptor is localized at presynaptic active zones from pyramidal cells to somatostatin-containing interneurons with postsynaptic ELFN1, and this interaction drives the rapidly facilitating nature of these synapses in the hippocampus and cortex.

OCNDS core features are conserved across variants, with loop-region mutations driving greater symptom burden.

Introduction: Okur-Chung Neurodevelopmental Syndrome (OCNDS) is an ultra-rare genetic disorder caused by mutations in the gene, which encodes the catalytic subunit of protein kinase CK2α. OCNDS is characterized by global developmental delay, intellectual disability, speech and language deficits, and other multi-system symptoms. Although prior reports have described considerable phenotypic variability, the relationship between specific CK2α variant locations and symptom presentation remains poorly defined.

Neuron-to-glia signaling drives critical period experience-dependent synapse pruning.

Critical periods enable early-life synaptic connectivity optimization whereby initial sensory experience remodels circuits to a variable environment. In the Drosophila juvenile brain, synapse remodeling occurs within the precisely-mapped olfactory circuit, which has an extensively characterized, manageably short (< 1 week) critical period. In this brain circuit, single receptor olfactory sensory neuron (OSN) classes synapse onto single projection neurons extending to the central mushroom body learning/memory center.

Advanced Age in Mice Exacerbates Sepsis-Induced Inflammation, Vascular Permeability, and Multi-Organ Dysfunction.

Sepsis is a life-threatening syndrome marked by a dysregulated immune response to an infection and significant endothelial vascular permeability, often leading to multi-organ failure. Elderly patients are particularly vulnerable to sepsis, with higher morbidity and mortality rates. We hypothesized that advanced age exacerbates sepsis-induced inflammation and endothelial vascular permeability, resulting in a delayed recovery, persistent inflammation, and sustained organ injury.

Discovery of a Novel sp‑Rich M Positive Allosteric Modulators (PAMs) Chemotype via Scaffold Hopping.

The M receptor has long been investigated as a promising CNS drug target, yet further research is essential to fully elucidate compound's Pharmacodynamic (PD) as well as Toxicokinetic (TK) effects. In this context, the development of structurally diverse and high-profile M PAM tool compounds remains highly valuable, as existing advanced tools exhibit notable structural similarity. One approach that can be considered during scaffold hopping exercise and can improve drug-like properties is to introduce additional sp carbon atoms and increase Fsp values; the fraction of sp hybridized carbons.

Precision targeting of C3+ reactive astrocyte subpopulations with endogenous ADAR in an iPSC-derived model.

Astrocytes play pivotal roles in maintaining neural architecture and function. However, their pronounced heterogeneity, especially in reactive states where distinct subtypes can adopt potentially opposing functions (e.g.

High-density Multielectrode Array Recordings of Retinal Waves Using An Electrophysiology Platform.

Spontaneous retinal waves are a hallmark of retinal network activity during development, playing a crucial role in the formation of the visual system by influencing the refinement of axons, permeability of vasculature, and overall maturation of neural circuits. These waves are commonly studied in ex vivo retinal preparations using multielectrode arrays (MEAs), which enable electrophysiological recordings of large populations of retinal ganglion cell (RGC) activity. MEA-based electrophysiology has become a powerful tool due to its ease of use to rapidly collect high-throughput data, thus making it ideally suited to study retinal activity in a variety of experimental conditions.

White matter microstructure and macrostructure brain charts across the human lifespan.

Normative reference charts are widely used in healthcare, especially for assessing the development of individuals by benchmarking anatomic and physiological features against population trajectories across the lifespan. Recent work has extended this concept to gray matter morphology in the brain, but no such reference framework currently exists for white matter (WM) even though WM constitutes the essential substrate for neuronal communication and large-scale network integration. Here, we present the first comprehensive WM brain charts, which describe how microstructural and macrostructural features of WM evolve across the lifespan, by leveraging over 26,199 diffusion MRI scans from 42 harmonized studies.