Frontiers in Cellular Neuroscience最新文献

[This corrects the article DOI: 10.3389/fncel.2025.1590493.].

Introduction: The external segment of the globus pallidus (GPe) is traditionally viewed as a relay nucleus within the indirect basal ganglia pathway. However, a subpopulation of GPe neurons projects directly to the striatum, raising questions about their compartmental and cell-type-specific targeting.

Methods: To address this issue, we employed neural tracing and ex vivo whole-cell patch-clamp recordings with optogenetics using adeno-associated viral vectors in rats. Anatomical observations and intersectional labeling techniques were applied to examine spatial relationships of projections among the striatum, GPe, and ventral thalamus.

Results: GPe axons exhibited a strong bias toward the matrix compartment of the striatum. This biased projection originated from both subthalamic nucleus-targeting and striatum-targeting GPe neurons. In contrast, striatal projections to the GPe arose from both matrix and striosome compartments. Optogenetic stimulation of GPe axons elicited inhibitory postsynaptic currents in medium spiny neurons (MSNs) and cholinergic interneurons (CINs) in the matrix compartment. Cesium-based recordings indicated distal synaptic contacts in MSNs. Anatomical data also revealed proximal appositions of GPe axons to CIN somata and dendrites. Excitatory inputs from motor cortical areas and ventral thalamic nuclei also preferentially targeted the matrix. Furthermore, optogenetic stimulation of ventral thalamic axons elicited excitatory postsynaptic currents in GPe neurons. Intersectional labeling revealed substantial overlap between striatal neurons and axons of GPe neurons, both of which were innervated by the same population of ventral thalamic neurons.

Discussion: These findings suggest that convergent cortical and thalamic excitation of both the striatum and GPe may induce feedforward inhibition within the striatal matrix, particularly onto CINs. This mechanism may contribute to the fine-tuning of striatal output in motor-related basal ganglia circuits.

The anterior retrosplenial cortex (aRSC) functions as a hub that integrates multimodal sensory inputs into associative recognition memories. Although the aRSC receives dense serotonergic projections from the raphe nuclei, the role of serotonin in its function remains poorly understood. Among serotonergic receptors, 5-HT2A receptors (5-HT2ARs) are highly expressed in cortical regions, including the aRSC, and have been implicated in the modulation of cognitive processes. Based on our previous work demonstrating the involvement of the aRSC in recognition memory, here we investigated the contribution of 5-HT2ARs (memory) during different phases of the object recognition (OR) task in rats. We found that selective blockade of 5-HT2ARs in the aRSC differentially affected acquisition, consolidation, and retrieval. These findings identify 5-HT2ARs in the aRSC as critical modulators of recognition memory processing and suggest that their dysregulation could contribute to cognitive impairments observed in conditions such as Alzheimer's disease.

Introduction: Studies indicate that pattern separation for spatial and object information involves structures of the temporal cortex (lateral entorhinal and perirhinal cortices) and hippocampus (dentate gyrus and CA3), which are particularly sensitive to aging. However, little is known about how the hippocampal network, the anteroposterior axis of these regions, and the excitatory-inhibitory circuit contribute to the recognition and separation of object patterns.

Methods: This study investigated the expression of c-Fos and PV along the anteroposterior axis of the hippocampus in a multi-trial task to assess the recognition of novel objects and recognition of novel objects with different levels of similarity. Five groups of animals performed tasks with different similarity demands (NOR, DIST, 25, 50, 75%).

Results: The data showed that conditions of greater similarity led to increased c-Fos expression in CA3c and Hilus in the rostral hippocampus. Graph analysis revealed that hippocampal networks became more densely interconnected and efficient as object similarity increased. Furthermore, different patterns of cluster organization emerged depending on task demands. Besides, the granule cell layer along the dorsoventral axis exhibited greater activation of inhibitory neurons (PV+/c-Fos+) under conditions of higher similarity. Differential inhibitory/excitatory control of the DG-CA3 microcircuit network is seen across conditions. Modeling the DG layers revealed robust control of GCs through direct and indirect effects of interneurons present in the hilus and granule layer. Bidirectional direct and indirect effects of MCs on GCs were observed.

Discussion: These results contribute to our understanding of how brain networks and DG excitatory/inhibitory microcircuits are jointly engaged in object recognition memory and disambiguation of overlapping inputs.

Introduction: Serotonin (5-HT) is a neurotransmitter that is involved in retinal development, physiology, and vision, yet the specific contribution of individual 5-HT receptors to retinal function is poorly characterized. We identified 5-HT receptor 1B (Htr1b) as a potential key regulator of serotonergic signaling in the retina.

Methods: Htr1b localization was examined using RNAseq and in situ labeling. Retinal structure was assessed using histology and SD-OCT. Visual function was evaluated using optomotor behavioral experiments. Retinal function was characterized in vivo using electroretinography (ERG) and ex vivo using multielectrode array (MEA) recordings.

Results: Htr1b transcript and HTR1B protein localized primarily to the inner retina and RGCs. While Htr1b ^-/- mice displayed normal retinal anatomy, they exhibited visual deficits in contrast sensitivity and visual acuity. ERG recordings revealed that RGCs had latency delays and reduced sensitivity to changes in light intensity. MEA analysis showed altered RGC firing patterns and increased variability following 5-HT application. These effects were cell-type specific: Htr1b ^-/- ON RGCs showed elevated basal firing rates while Htr1b ^-/- OFF RGCs showed reduced 5-HT responses.

Discussion: These findings demonstrate that Htr1b is necessary for normal retinal serotonergic signaling and contributes to the regulation of RGC excitability and visual sensitivity.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor linked to the control of immunological responses. Although AhR has been investigated in relation to lipopolysaccharide (LPS) peripheral inflammation, its role in LPS-induced, astrocyte-mediated inflammation in vivo is unknown. This study explores the effect of AhR deletion on astrocyte reactivity and neuroinflammation responses to lipopolysaccharide (LPS). The results show that AhR loss aggravates LPS-induced inflammatory responses using a AhR germline knockout (AhRKO) mouse by increasing pro-inflammatory cytokines levels (TNF-α, IL-1β) and inducible nitric oxide synthase (iNOS) in both primary astrocyte cultures and the mouse hippocampus. Morphologically, astrocytes and microglia from AhRKO mice show increased soma size following LPS injection, suggesting increased glial activation. In addition, AhRKO mice displayed more severe weight loss and locomotor impairment behaviorally following a single systemic LPS injection. Elevated nuclear translocation of NF-κB p65 in AhR-deficient astrocytes provides a potential mechanism for elevated pro-inflammatory signaling. These results emphasize an immunomodulatory role for AhR in reducing astrocyte-driven inflammation and identify AhR as possible therapeutic target for neurodegenerative illnesses linked with neuroinflammatory responses.

Introduction: Fragile X Syndrome (FXS), the most common genetic cause of intellectual disability and autism spectrum disorder (ASD), results from silencing of the FMR1 gene and consequent loss of Fragile X Messenger Ribonucleoprotein (FMRP). FMRP deficiency disrupts neural development, leading to behavioral and motor deficits associated with striatal dysfunction. Although structural and functional abnormalities in striatal projection neurons (SPNs) have been observed in adult Fmr1 knockout mice (Fmr1-/y), their developmental onset and contribution to early FXS pathophysiology remain unknown.

Methods: We examined the postnatal maturation of SPNs in the dorsomedial striatum (DMS) of Fmr1-/y mice, assessing glutamatergic synaptic inputs and intrinsic excitability using whole-cell electrophysiology.

Results: During postnatal development, Fmr1 deficient SPNs display normal synaptic and intrinsic properties, consistent with typical maturation. In contrast, by P60, Fmr1-/y SPNs exhibit pronounced hyperexcitability in both dopamine D1 receptor-expressing SPNs (D1-SPNs) and D2 receptor-expressing SPNs (D2-SPNs), with more pronounced effects in D1-SPNs. Chronic aripiprazole treatment, a widely prescribed therapy for behavioral symptoms in FXS, fails to normalize SPN excitability, suggesting limited efficacy in addressing core SPN dysfunction.

Discussion: These findings reveal that DMS SPN hyperexcitability in Fmr1-/y mice emerges after early postnatal development, pointing to a progressive trajectory of striatal abnormalities. In addition, these results underscore the importance of developmental timing in FXS pathophysiology and emphasize the need for targeted interventions to address SPN dysfunction.

Mutations in the transmembrane serine protease 3 gene (TMPRSS3) cause non-syndromic hearing impairment, with congenital (DFNB10) or late childhood onset (DFNB8). In some reports, these patients were found to have lower speech comprehension scores with cochlear implants (CIs) compared to CI users with other etiologies. Since CIs electrically stimulate spiral ganglion neurons (SGNs) to activate the auditory pathway, TMPRSS3 deficiency was presumed to cause a dysfunction or degeneration of these cells, of which type I SGNs form the predominant group. Here, we revisited the expression pattern of Tmprss3 in the developing and mature mouse inner ear on mRNA level with quantitative few-cell PCR and RNAscope, and on protein level with immunohistochemistry with an anti-TMPRSS3 antibody validated on knock-out tissue. In the organ of Corti, we demonstrate expression of Tmprss3 in inner and outer hair cells, particularly in the stereocilia, and in pillar cells. Furthermore, expression of this gene in root cells of the lateral wall close to the stria vascularis indicates a potential function in K⁺ recycling, and expression in the spiral limbus may be linked to the generation of the tectorial membrane. Within Rosenthal's canal, in immature tissue, Tmprss3 was diffusely expressed in all SGNs, but in the mature ear, in type I SGNs we found only minor mRNA amounts with qPCR, RNAscope, and no specific immunolabeling. In contrast, in type II SGNs Tmprss3 expression is enhanced during maturation. We hypothesize that the background levels of Tmprss3 expression in type I SGNs are not directly responsible for the vitality of these neurons, and that indirect effects, like signaling cascades dependent on TMPRSS3 in other cell types, are crucial for type I SGN function and survival.

Glioblastoma (GBM) progression is linked to aquaporin-4 (AQP4), whose functions extend beyond water transport to influence perivascular architecture, immune modulation, edema, and treatment response. In the healthy brain, AQP4 is highly polarized at astrocytic endfeet, supporting perivascular fluid exchange and glymphatic clearance. In GBM, AQP4 is frequently upregulated and mislocalized, correlating with blood-brain barrier (BBB) disruption, impaired directional fluid movement, and peritumoral edema. Peritumoral astrocytic mislocalization of AQP4, together with tumor mass effect, compromises glymphatic function by distorting perivascular spaces and compressing cerebrospinal fluid (CSF)-Interstitial fluid (ISF) exchange zones. We review evidence that AQP4 isoforms (M1 vs. M23) differentially shape motility and membrane organization, and we outline how AQP4-linked signaling axes (e.g., indoleamine 2,3-dioxygenase 1 (IDO1)/tryptophan 2,3-dioxygenase (TDO)-kynurenine-aryl hydrocarbon receptor (AhR) can bias pro-invasive states and immunosuppressive niches enriched with M2-like macrophages). We integrate a four-zone perivascular framework to localize where GBM most perturbs periarterial and perivenous pathways, as well as meningeal lymphatic outflow. Finally, we discuss therapeutic directions spanning AQP4 modulation, isoform balance, and BBB-bypassing delivery strategies. Overall, AQP4 emerges as a mechanistic hub connecting BBB instability, glymphatic impairment, edema, immune evasion, and invasion in GBM.

Spinal motoneurons are the final output of spinal circuits that engage skeletal muscles to generate motor behaviors. Many motoneurons exhibit bistable behavior, alternating between a quiescent resting state and a self-sustained firing mode, classically attributed to plateau potentials driven by persistent inward currents. This intrinsic property is important for normal movement control, but can become dysregulated, causing motor function deficits, like spasticity. Here we use a conductance-based single-compartment model, together with mouse spinal slice recordings, to investigate the ionic interactions underlying motoneuron bistability. We show that synergistic interactions among high-voltage-activated L-type Ca²⁺ current (I _CaL ), calcium-induced calcium release (CICR) and the Ca²⁺-activated non-specific cation current (I _CAN ) constitute a minimal mechanistic core that produces plateau potentials and bistable firing. Within this framework, the persistent sodium current (I _NaP ) promotes plateau generation, in contrast to the Ca²⁺-dependent K⁺ current (I _KCa ) which opposes it. These results delineate ionic dependencies at the level of interactions rather than spatial localization and provide a tractable basis for interpreting altered motoneuron excitability in disease.