Neuron最新文献

Microglia arise from yolk sac progenitors and are thought to persist throughout life with minimal input from adult hematopoiesis. However, whether brain-engrafted monocyte-derived macrophages (MDMs) exist at homeostasis and during turnover and how they function relative to yolk-sac-derived microglia (YSMs) remain unsettled. Here, we combine lineage tracing, pharmacological microglia depletion, and multi-omics profiling to define the ontogeny, identity, and function of brain parenchymal macrophages. Despite sharing the parenchymal milieu, MDMs display transcriptional and epigenetic landscapes distinct from YSMs. Fate-mapping reveals that brain-engrafted MDMs transiently express CD206, echoing a developmental stage of microglial precursors. MDM engraftment and polarization are modulated by interleukin (IL)-34 and C-C chemokine receptor 2 (CCR2). Furthermore, parabiosis and skull-flap transplantation reveal that both blood and skull marrow supply the niche, yielding origin-biased MDM states. Functionally, MDM engraftment enhances cuprizone-mediated demyelination. Together, our study defines the origins, molecular features, and context-dependent roles of brain parenchymal macrophages across homeostasis, turnover, and central nervous system (CNS) pathology.

Amyotrophic lateral sclerosis (ALS) is genetically and clinically heterogeneous, yet convergent pathogenic mechanisms remain poorly defined. A CRISPR-Cas9 screen identified phosphoglycerate mutase-5 (PGAM5) as a common mediator of ALS pathogenesis. PGAM5 activates the mitochondrial integrated stress response (mtISR) via dephosphorylation of metallopeptidase OMA1 at Ser223 and Ser237, thereby driving neuromuscular junction disruption and motor deficits. We show that PGAM5 is a substrate of valosin-containing protein (VCP) and is consistently elevated in spinal cords from sporadic ALS patients, in human spinal cord organoids derived from sporadic or familial ALS, and in ALS mouse models. The disruption of PGAM5-OMA1 interaction by a selective inhibitor (TAT-PO1) or pharmacological inhibition of PGAM5 with telmisartan suppresses mtISR activation and ameliorates ALS-related phenotypes by reshaping mtISR outputs in a manner distinct from those elicited by activation of translation initiation factor 2B (eIF2B). These findings establish PGAM5 as a convergent and actionable therapeutic target across ALS subtypes.

I discuss human single-neuron recordings and the discovery of concept cells-i.e., neurons representing specific concepts in the hippocampus and surrounding cortex-about 20 years ago. I then present the main properties of concept cells and show how these neurons are involved in forming and storing memories in coordination with complementary neocortical representations. Finally, I compare the response properties of concept cells with those reported in the hippocampus of other species and argue that the abstract representation by concept cells is exclusively human and might be a cornerstone of human cognitive abilities, such as our power for high-level abstract thinking and generalization.

How hindbrain circuits integrate peripheral and central signals to regulate complex oral behaviors is poorly understood. In rodents, gnawing is essential for localized tooth wear to offset lifelong incisor growth. Whether this process relies on specific sensory input to guide localized tooth wear and is actively regulated by neural mechanisms remains unresolved. Here, we identify somatostatin-expressing neurons in the spinal trigeminal nucleus oralis as a central relay distributing tactile input to motor execution and motivational circuits. These neurons receive input from a genetically distinct population of S100b⁺ Aβ low-threshold mechanoreceptors that innervate the incisor periodontium and project to both jaw-closing motor neurons and, via the parabrachial nucleus, the ventral tegmental area. Disruption of this pathway abolished gnawing and resulted in severe malocclusion, while activation triggered dopamine release in the nucleus accumbens. Our findings redefine dental alignment as an active, touch-dependent, circuit-governed process and reframe malocclusion as a sensorimotor-motivational integration disorder.

Preclinical Alzheimer's disease (AD) is associated with distressing neuropsychiatric symptoms (NPSs) that may accelerate progression toward dementia. Existing approaches probe the symptom-level domain-general or domain-specific neural correlates of NPSs. However, the field lacks process-oriented models of symptom emergence for targeted treatment. We propose one pathway for symptom emergence involving the disruption of emotion regulation (ER) systems by early AD pathology. AD pathology in the ventral anterior cingulate cortex-ventromedial prefrontal cortex disrupts model-free ER that modulates negative valuations using experience-dependent reinforcement learning (e.g., fear extinction), leading to increased negative valuations and negative affect. We further propose that model-based ER competes for overtaxed executive resources and is less successful in preclinical AD, particularly in demanding real-world contexts. These changes lead to a shift toward negative affect, leading to divergent trajectories of NPSs depending on critical moderators. We discuss implications for intervention to improve NPSs and potentially slow dementia progression.

Dimensionality reduction methods are widely used in neuroscience to investigate two complementary aspects of neural activity: the distribution of single-neuron functional properties and the low-dimensional collective dynamics of population activity. However, how do these two aspects of neural activity relate to the structure of the underlying neural circuit? In this work, we connect circuit structure, single-neuron functional properties, and emerging low-dimensional dynamics in spiking recurrent network models. Our models explain how topologically distinct circuit structures can produce equivalent low-dimensional dynamics. Despite this degeneracy, we find that circuit structure imposes specific constraints on both the low-dimensional dynamics of population activity and the distribution of single-neuron functional properties. These constraints yield simple criteria for comparing network models with observed neural activity. Our modeling framework not only links classical models of cortical circuits to the more recent notion of neural manifolds but also paves the way for designing tractable models of population dynamics that are better aligned with neural recordings.

Anxiety disorders are the most prevalent mental disorders globally, yet current treatments remain limited. Histamine is an evolutionarily conserved neuromodulator recently implicated in neuropsychiatric disorders. However, whether and how histaminergic signaling dynamically represents emotionally salient information and regulates anxiety remain largely unknown. We show that anxiogenic exposure triggers region-specific dynamic histamine release in ventral hippocampal CA1 (vCA1). The vCA1-projecting histaminergic circuit exhibits similar dynamics and bidirectionally regulates anxiety through engaging astrocytic H3 receptors (H3Rs). Genetic ablation of astrocytic H3Rs attenuates astrocytic responsiveness to anxiety-related contexts and directly promotes anxiety via gliotransmitter γ-aminobutyric acid (GABA) signaling. Notably, chronic stress induces adaptive upregulation of vCA1 astrocytic H3R expression, while further potentiation of astrocytic H3R signaling is sufficient to attenuate maladaptive anxiety. These findings collectively establish that vCA1 astrocytic histaminergic signaling governs natural anxiolysis in both normal and maladaptive anxiety states, identifying astrocytic H3Rs as crucial emotional regulators and a potential therapeutic target for anxiety disorders.

In this interview with Neuron, David Sussillo reflects on his journey from a disadvantaged childhood to becoming a leading computational neuroscientist and AI researcher. He discusses the development of FORCE learning, advances in neural network interpretability, the interplay between academia and industry, and advice for aspiring scientists from non-traditional backgrounds.