Neuron最新文献

Following central nervous system injury, astrocytes form borders that were traditionally regarded as physical barriers. Emerging evidence demonstrates their capacity to regulate inflammation and repair; however, the specific characteristics of these border astrocytes and their interactions with immune cells remain insufficiently characterized. Using single-cell sequencing and spatial transcriptomics, we identified astrocytes expressing the interferon-inducible protein bone marrow stromal cell antigen 2 (BST2) enriched at injury boundaries that promote microglial recruitment via C3/C3aR signaling. Astrocyte-specific Bst2 knockout reduced astrocyte-microglia interactions and attenuated border formation, correlating with early neurological improvement after stroke. Mechanistically, BST2 enhanced C3 expression through protein kinase C-βII (PKCβII) phosphorylation. Moreover, treatment with a BST2 monoclonal antibody diminished astrocyte-microglia interactions and improved neurological function. Together, these findings highlight the pivotal role of astrocyte-microglia interactions in lesion border formation and suggest that BST2 may represent a therapeutic target to modulate these interactions and reduce early brain injury after stroke.

The lifetime prevalence of mood disorders such as major depressive disorder (MDD) is thought to approach up to 50% of the world's population. Traditionally, research into the mechanisms of these disorders has focused on neurotransmission, but emerging evidence highlights neuroimmune interactions-the molecular signaling between immune and brain cells-as key regulators of brain plasticity, affective behavior, and potential vulnerability to mood disorders. Chronic stress models have unearthed how immune cell responses modify neural circuit activity, synaptic connectivity, and behaviors relevant for mood disorders by acting on brain-resident cell types. This perspective synthesizes basic principles of neuroimmune communication derived from animal studies relevant for mood disorders and assesses their relevance in MDD and post-traumatic stress disorder (PTSD). We describe cellular neuroimmune interactions important for behavior as well as the molecular mechanisms that govern immune-brain plasticity across different cell types. We also explore how therapeutic interventions, including anti-inflammatory biologics and psychedelics, can target these pathways. Finally, we chart how the field could dissect neuroimmune interactions across biological scales in the near future by highlighting the conceptual frontiers and emerging technologies. Understanding the modulation of neuroimmune interactions promises to inform next-generation treatments for mood disorders.

The retrotransposons and endogenous retroviruses (ERVs) that contain long terminal repeat (LTR) sequences are a subset of transposable elements (TEs) that make up around 8% of the human genome. These retroelements (retroTEs) are derived from ancient retroviral infections or retrotransposons that have become permanently integrated into the germline and include domesticated retroTEs, such as the neuronal gene Arc. Until recently, limited tools and difficulties in mapping retroTEs have made it challenging to study these elements in detail. However, recent advances have revealed that retroTEs play a role in both human disease and physiological processes in the brain. Here, we highlight studies showing that retroTE nucleic acid and protein products perform unique functions in intercellular signaling and nervous system dysfunction. We discuss how these elements play critical roles in complex processes such as cognition and how future work will provide insight into neurological disorders.

In this issue of Neuron, Zhang et al.¹ identified a subset of BST2-high astrocytes that emerge at the ischemic injury border and promote microglial recruitment through the C3-C3aR pathway. These findings highlight BST2 as a key modulator of astrocyte-microglia communication and a potential therapeutic target for CNS injury.

Increasing evidence suggests that attention varies rhythmically, phase locked to ongoing cortical oscillations. Here, we report that the phase of theta oscillations (3-6 Hz) in the frontal eye field (FEF) is associated with the spatiotemporal variation of information readout from working memory (WM). Non-human primates were briefly shown a sample array of colored squares. A short time later, they viewed a test array and were rewarded for identifying which square changed color (the target). Behavioral performance varied systematically with theta phase at the time of test array onset, as well as with the target's location. This is consistent with theta "scanning" across the FEF and thus visual space from top to bottom. Theta was coupled, on opposing phases, to both spiking and beta (12-20 Hz). These results could be explained by a wave of activity that moves across the FEF, modulating the readout of information from WM.

Follistatin-like 1 (FSTL1) is a signaling molecule that modulates energy metabolism in peripheral tissues and is also expressed in the brain. However, whether hypothalamic FSTL1 regulates carbohydrate/lipid metabolism and energy balance remains unknown. Here, we show that FSTL1 is enriched in the hypothalamus, especially the arcuate nucleus (ARC). FSTL1 expression is decreased in diet-induced obese (DIO) and db/db mice. Agouti-related peptide (AgRP) neuron-specific Fstl1 deletion increased food intake, decreased energy expenditure, and impaired insulin sensitivity in DIO mice. Conversely, Fstl1 overexpression in AgRP neurons resulted in the opposite phenotypes. Insulin signaling was required for the anti-obesity effect of hypothalamic FSTL1. Intranasal FSTL1 delivery promoted weight loss and improved insulin sensitivity in DIO mice. Mechanistically, FSTL1 interacts with Akt, an intracellular mediator of insulin signaling, to inhibit forkhead box protein O1 (FoxO1) nuclear translocation. Our findings identify hypothalamic FSTL1 as a key mediator counteracting DIO and provide a potential pharmacological strategy for obesity-related metabolic disorders.

Sensory afferents are major interoceptive pathways for organ-brain communication. Within the distal colon, dorsal root ganglia (DRGs) afferents regulate key gut physiology. Inflammation causes hypersensitivity of DRG pathways, leading to visceral pain. However, whether enteric neurons contribute to interoception and visceral pain remains unclear. Here, we surveyed the DRG innervation along the gastrointestinal tract in mice and found extensive associations between DRG terminals and enteric neurons. Optogenetic activation of different DRG terminals in the distal colon elicited variable degrees of behavioral responses, but only designated subpopulations induced aversion. Notably, optogenetic activation of colon cholinergic, but not nitrergic, enteric neurons signaled through the DRG-spinal pathway to evoke a non-aversive nociceptive-like reflex. Acetylcholine is part of the enteric-DRG signaling. Remarkably, inflammation shifted the nature of the enteric-DRG pathway from non-aversive to aversive. These findings expand the previous understanding of DRG-mediated visceral sensation, highlighting the contribution of enteric neuron-DRG communication to inflammation-induced visceral pain.

In this issue of Neuron, Han et al.¹ leverage a change-identification working memory task coupled with electrophysiological recordings in the macaque frontal eye field to show that information retrieval from working memory varies rhythmically with neural theta oscillations.

In this issue of Neuron, Li et al.¹ show that follistatin-like 1 (FSTL1) emerges as a critical hypothalamic insulin sensitizer, whose pharmacological targeting attenuates body weight gain and improves systemic glucose metabolism, highlighting brain insulin signaling amplification as a promising strategy against obesity and associated metabolic disorders.