Trends in Neurosciences最新文献

Monoaminergic neurotransmission has long been recognized as essential for the development, maintenance, and plasticity of the nervous system, with classical models defining serotonin, dopamine, and histamine as extracellular messengers acting through cell surface receptors. Broadening this view, emerging evidence reveals that biogenic amines also covalently modify proteins, a process termed 'monoaminylation', to directly influence intracellular signaling. The discovery of non-canonical monoamine signaling across subcellular compartments offers new insights into brain-body communication. Here, we review the evolving signaling landscape of protein monoaminylations and highlight new chemical-biological tools for probing their impact on neural development, plasticity, and disease.

Microglia are the brain's primary innate immune cells, which maintain neural homeostasis through surveillance, debris clearance, and synaptic remodeling. Dark microglia represent a distinct state of microglia that came into recent focus due to their excessive physical contact with synapses in contexts of pathological synapse loss, predominantly in neurodegenerative conditions, such as Alzheimer's disease. Dark microglia are identified by their unique ultrastructural features, exhibiting a dark, condensed appearance under electron microscopy. They display signs of cellular stress and appear to be engaged in synaptic pruning. Here, we review recent advances in understanding these intriguing cells in the mammalian brain, from new molecular insights into their origin to their emerging functional roles across the lifespan, in both health and disease.

Neural processing is often categorized as externally or internally focused. Though commonly treated as poles of a single dimension, we delineate how the terms 'external' and 'internal' refer to independent concepts at the levels of cognitive modes, representational contents, and sensory origins. Separating these levels brings theoretical clarity and opens unexplored questions.

Spatial cognition in mammals relies on various spatially tuned cell types in the hippocampus and associated brain regions. Recent studies have increasingly explored the developmental timelines of these cells, their characteristics during early life, and the developmental origins of their functional heterogeneity in adulthood. In this review we discuss these findings and propose that the emergence and properties of spatially tuned cells across various developmental stages are shaped by the sequential maturation of multiple sensory and motor systems, as well as by the maturation of local inhibitory circuits. In addition, sensory and navigation experiences crucially influence the development of spatial navigation and episodic memory circuits. Finally, we highlight the diversity of cell types during development, and discuss how this diversity contributes to the functional heterogeneity of spatially tuned cells in adulthood.

The visual system can function across variable scene statistics and behavioral contexts. This flexibility arises in part from neural feedback, which shapes visual processing to align with prevailing stimulus conditions and behavioral goals. In the fruit fly Drosophila melanogaster, extensive genetic and connectome resources allow feedback connections of identified cells to be linked to their functions in the visual system. Here, we review key mechanisms and functions of feedback in the Drosophila visual system, drawing parallels to vertebrate models, where feedback also plays an important role in visual processing. We conclude by arguing that connectomes are critical in this task and that cracking feedback circuits in flies can help guide our understanding of feedback in larger brains.

Synaptic vesicle glycoprotein 2 (SV2) isoforms are crucial for synaptic function and neurotransmission. Although their precise physiological roles remain unclear, SV2 proteins serve as receptors for several botulinum neurotoxins (BoNTs) and are also the targets of anticonvulsants. Recent cryo-electron microscopy (cryo-EM) studies have greatly advanced our understanding of the structure and function of both SV2 proteins and BoNTs. The findings unveiled the molecular architectures of BoNTs, their receptors SV2A and SV2B, and how anticonvulsants bind to SV2A and how these interactions can be modulated allosterically. Additionally, the studies revealed a conserved binding mode in the interaction between BoNT/A and SV2 proteins, which involves significant conformational changes in the toxin. In this review, we will discuss these findings and their implications.

Sex-specific chemosensory behaviors arise from differences in how males and females detect and process environmental chemical cues, including pheromones, which drive sex-appropriate behaviors essential for reproduction across many species. This review compares neural circuits in Caenorhabditis elegans, Drosophila, and rodents that generate sexually dimorphic pheromone responses, spanning peripheral detection, relay centers, and central integration. Recent connectomic and circuit-level analyses reveal how internal states modulate these pathways, adding an additional layer of context-dependent, sex-specific modulation. By synthesizing mechanisms across species, we highlight conserved principles and lineage-specific adaptations, offering an integrative framework for understanding how sex differences are embedded in chemosensory neural systems and setting the stage for future work on sexually dimorphic behaviors.

In a recent study, Goueytes and colleagues combined computational modeling with intracranial recordings to dissect the neural basis of confidence and changes of mind. They reveal a temporally organized, spatially distributed hierarchy of evidence accumulation, with pre-decisional signals in the pre-supplementary motor area (preSMA) and post-decisional signals in the insula. This reframes metacognition as a distributed and dynamic process.

Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.

Apathy is a common symptom across a wide range of neurodegenerative and psychiatric conditions, characterised by a loss of goal-directed action. It is associated with faster rates of cognitive and functional decline, poor prognosis, and high caregiver burden. Effective treatments remain elusive. In this article, we propose that apathy is not merely the result of actions becoming undesirable due to insufficient reward or an inflated sense of cost. Instead, actions become unnecessary due to a loss of prior precision on action outcomes in the context of the 'Bayesian brain'. We outline the theoretical background and current evidence to support this framework and propose testable hypotheses regarding the behaviour, neuroanatomy, and neuropharmacology of apathy.