Neuron最新文献

Pain relief is the most frequently reported motivation for opioid misuse, but it remains unclear how pain alters reward pathway function contributing to maladaptive opioid use and whether these neuroadaptations occur in a sex-specific manner. Here, we show that persistent inflammatory pain leads to augmented fentanyl self-administration in male, not female, rats. Wireless in vivo fiber photometry recordings and chemogenetic manipulations indicate that pain-facilitated fentanyl use is mediated by enhanced ventral tegmental area dopamine (VTA^DA) neuron responses during self-administration. In females, ovariectomy enhances fentanyl self-administration, but the protective effects of ovarian hormones are not solely mediated by estradiol per se. Instead, pain and high estradiol states-naturally occurring in intact females or artificially produced in males-suppress fentanyl self-administration and associated VTA^DA activity through VTA estrogen receptor beta signaling. These findings highlight the importance of assessing hormonal factors in opioid misuse liability in the context of pain.

Systems consolidation relies on coordination between hippocampal sharp-wave ripples (SWRs) and neocortical UP/DOWN states during sleep. However, whether this coupling exists across the neocortex and the mechanisms enabling it remains unknown. By combining electrophysiology in mouse hippocampus (HPC) and retrosplenial cortex (RSC) with wide-field imaging of the dorsal neocortex, we found spatially and temporally precise bi-directional hippocampo-neocortical interaction. HPC multi-unit activity and SWR probability were correlated with UP/DOWN states in the default mode network (DMN), with the highest modulation by the RSC in deep sleep. Further, some SWRs were preceded by the high rebound excitation accompanying DMN DOWN → UP transitions, whereas large-amplitude SWRs were often followed by DOWN states originating in the RSC. We explain these electrophysiological results with a model in which the HPC and RSC are weakly coupled excitable systems capable of bi-directional perturbation and suggest that the RSC may act as a gateway through which SWRs can perturb downstream cortical regions via cortico-cortical propagation of DOWN states.

In this issue of Neuron, Kong et al.¹ identify targetable natural killer-like T cells that seed the intact aged human and murine spinal cords and increase further after injury. These cells impede myeloid-cell-dependent wound healing in the aged injured cord through expressing natural killer cell granule protein 7 (NKG7).

A rare variant of Apolipoprotein E3 with neuroprotective properties has been identified in autosomal-dominant Alzheimer's disease. In this issue of Neuron, Chen et al.¹ show that direct interaction between this variant and tau blocks tau pathogenesis in rodent models.

In this issue of Neuron, Chen et al. identify a postprandial neuroimmune axis by which feeding-induced stimulation of the gastrointestinal tract triggers type 2 immunity in the lung.¹ This study hints that there are likely distinct sensory and motor circuits coordinated by the brain across different tissues to drive neuroinflammation.

Spinal cord injury (SCI) increasingly affects aged individuals, where functional impairment and mortality are highest. However, the aging-dependent mechanisms underpinning tissue damage remain elusive. Here, we find that natural killer-like T (NKLT) cells seed the intact aged human and murine spinal cord and multiply further after injury. NKLT cells accumulate in the spinal cord via C-X-C motif chemokine receptor 6 and ligand 16 signaling to clonally expand by engaging with major histocompatibility complex (MHC)-I-expressing myeloid cells. NKLT cells expressing natural killer cell granule protein 7 (Nkg7) disrupt myeloid-cell-dependent wound healing in the aged injured cord. Nkg7 deletion in mice curbs NKLT cell degranulation to normalize the myeloid cell phenotype, thus promoting tissue repair and axonal integrity. Monoclonal antibodies neutralizing CD8⁺ T cells after SCI enhance neurological recovery by promoting wound healing. Our results unveil a reversible role for NKG7⁺CD8⁺ NKLT cells in exacerbating tissue damage, suggesting a clinically relevant treatment for SCI.

The complexity of the human brain makes it challenging to understand the molecular mechanisms underlying brain function. Genome-wide association studies have uncovered variants associated with neurological phenotypes. Single-cell transcriptomics have provided descriptions of changes brain cells undergo during disease. However, these approaches do not establish molecular mechanism. To facilitate the scalable interrogation of causal molecular mechanisms in brain cell types, we developed a 3D co-culture system of induced pluripotent stem cell (iPSC)-derived neurons and glia, termed iAssembloids. Using iAssembloids, we ask how glial and neuronal cells interact to control neuronal death and survival. Our CRISPRi-based screens identified that GSK3β inhibits the protective NRF2-mediated oxidative stress response elicited by high neuronal activity. We then investigate the role of APOE-ε4, a risk variant for Alzheimer's disease, on neuronal survival. We find that APOE-ε4-expressing astrocytes may promote neuronal hyperactivity as compared with APOE-ε3-expressing astrocytes. This platform allows for the unbiased identification of mechanisms of neuron-glia cell interactions.

Gamma-band oscillations (GBOs) in the primary somatosensory cortex (S1) play key roles in nociceptive processing. Yet, one crucial question remains unaddressed: what neuronal mechanisms underlie nociceptive-evoked GBOs? Here, we addressed this question using a range of somatosensory stimuli (nociceptive and non-nociceptive), neural recording techniques (electroencephalography in humans and silicon probes and calcium imaging in rodents), and optogenetics (alone or simultaneously with electrophysiology in mice). We found that (1) GBOs encoded pain intensity independent of stimulus intensity in humans, (2) GBOs in S1 encoded pain intensity and were triggered by spiking of S1 interneurons, (3) parvalbumin (PV)-positive interneurons preferentially tracked pain intensity, and critically, (4) PV S1 interneurons causally modulated GBOs and pain-related behaviors for both thermal and mechanical pain. These findings provide causal evidence that nociceptive-evoked GBOs preferentially encoding pain intensity are generated by PV interneurons in S1, thereby laying a solid foundation for developing GBO-based targeted pain therapies.

Lung type 2 immunity protects against pathogenic infection, but its dysregulation causes asthma. Although it has long been observed that symptoms of asthmatic patients often become exaggerated following food intake, the pathophysiological mechanism underlying this postprandial phenomenon is incompletely understood. Here, we report that lung type 2 immunity in mice is enhanced after feeding, which correlates with parasympathetic activation. Also, local parasympathetic innervations exhibit spatial engagement with such immune responses mediated by group 2 innate lymphoid cells (ILC2s). Pharmacologic or surgical blockage of parasympathetic signals diminishes lung type 2 immunity. Conversely, chemogenetic manipulation of parasympathetic inputs and their upstream neurocircuit is sufficient to modulate those immune responses. We then show that the cholinergic receptor muscarinic 4 (Chrm4) for the parasympathetic neurotransmitter acetylcholine is expressed in mouse or human lung ILC2s, and the Chrm4 deletion mitigates ILC2-mediated lung inflammation. These results have revealed a critical neuroimmune function of the gut-brain-lung reflex.

The axon initial segment (AIS) is a highly specialized compartment in neurons that resides in between axonal and somatodendritic domains. The localization of the AIS in the proximal part of the axon is essential for its two major functions: generating and modulating action potentials and maintaining neuron polarity. Recent findings revealed that the incredibly stable AIS is generated from highly dynamic components and can undergo extensive structural and functional changes in response to alterations in activity levels. These activity-dependent alterations of AIS structure and function have profound consequences for neuronal functioning, and AIS plasticity has emerged as a key regulator of network homeostasis. This review highlights the functions of the AIS, its architecture, and how its organization and remodeling are influenced by developmental plasticity and both acute and chronic adaptations. It also discusses the mechanisms underlying these processes and explores how dysregulated AIS plasticity may contribute to brain disorders.