Aging is a risk factor for neurodegenerative disorders, but the molecular link between neuronal aging and neurodegeneration remains unclear. Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms. Striatal medium spiny neurons (MSNs) are mainly affected in HD, but how aging contributes to MSN degeneration remains uncertain. Using directly converted MSNs from fibroblasts of HD patients (HD-MSNs), we studied age-related pathological features, including neuronal cell death, mutant huntingtin (mHTT) aggregation, and DNA damage in HD. In this study, through transcriptomic analysis of longitudinally aged MSNs and HD-MSNs, we identified four upstream regulators, NFKB1, SOD1, IRF3, and REST, that modulate downstream gene expression in aged MSNs. Among these, knocking down NFKB1 significantly reduced HD pathologies in HD-MSNs, while overexpressing NFKB1 reversed these protective effects. Overall, these results identify NFKB1 as a key age-associated upstream regulator whose downregulation confers neuronal resilience and is a potential therapeutic target in HD.
Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, with no definitive cure currently available. Within the basal ganglia–thalamocortical circuitry, PD is characterized by an imbalance between antikinetic beta oscillations (13–35 Hz) and prokinetic gamma oscillations (60–90 Hz). While the pathological features and mechanisms underlying abnormal beta activity have been extensively studied, alterations in gamma oscillations remain much less well understood. Emerging evidence indicates that different forms of gamma activity are disrupted in PD and associated with symptoms such as dyskinesia, gait impairment, and rapid eye movement (REM) sleep behavior disorder. This review summarizes current clinical and preclinical evidence of aberrant gamma oscillations in PD, discusses underlying mechanisms including parvalbumin interneuron dysfunction, basal ganglia circuit imbalance, and impaired neurovascular coupling, and summarizes how current therapeutic approaches for PD modulate gamma activity and potentially influence clinical outcomes.
Protein Tyrosine Phosphatase Receptor Type O (PTPRO) is a synaptic cell adhesion molecule that is essential for synapse formation in vitro; however, its in vivo role remains unclear. Using PTPRO-knockout mice, we found that PTPRO deletion reduced the number of synapses and impaired both excitatory and inhibitory synaptic transmission. PTPRO knockout also disrupted hippocampal long-term potentiation and caused learning and memory deficits in the water maze as well as in fear conditioning. Notably, overexpression of the N-terminal extracellular domain of PTPRO rescued the frequencies of miniature excitatory postsynaptic currents and inhibitory postsynaptic currents, indicating that this domain is required to regulate synapse number and transmission. Collectively, these data demonstrate that PTPRO is essential for maintaining synapse number, synaptic transmission, long-term potentiation, and learning and memory functions in vivo.
Dexmedetomidine (DEX) induces a distinct state of “arousable sedation,” yet the neural circuits that sustain arousal capacity remain unclear. Here, we identified that 40 μg/kg DEX produced sedation from which animals could be transiently aroused by tactile stimulation of the back, whereas 100 μg/kg induced deeper, unresponsive sedation. Functional mapping revealed selective activation of the central medial thalamus (CMT). Fiber photometry further confirmed that DEX dose-dependently and selectively activated glutamatergic neurons in the CMT while simultaneously suppressing activity in other thalamic regions. Chemogenetic inhibition of CMT glutamatergic neurons deepened DEX sedation and impaired tactile‑stimulation-induced arousal following administration of 40 μg/kg DEX, whereas activation of CMT glutamatergic neurons under a high-dose DEX (100 μg/kg) attenuated sedation and restored tactile responsiveness. Together, these results establish the CMT as a critical thalamic node for maintaining arousal capacity during DEX sedation.
Color perception serves crucial ecological functions in many species. While color coding (e.g., a hue map) has been found throughout the visual pathway, its causal link to perception remains elusive. Here, we trained macaques to perform a color identification task using psychophysical paradigms. In a two-alternative forced-choice (2-AFC) digital task, the animals discriminated between two opponent hues (red vs. green or yellow vs. blue). Microstimulation using a low current (≤50 μA) delivered to the early visual cortex (EVC) frequently biased the animals' perceptual choices toward the preferred hue of the stimulated neurons, indicating a causal influence of local neuronal activity on perceptual decisions. In an analog, eight-category "rainbow" task, microstimulation also induced significant but more variable perceptual shifts. Stronger currents, presumed to introduce more noise, impaired behavioral sensitivity in both tasks, indicating that local neuronal activity is causally necessary for color perception. Our findings provide direct evidence that precise manipulation of the labeled-line chromatic code in the EVC is crucial for producing subjective color perception.
Yawning coupled with penile erection is a conserved neurobehavioral syndrome mediated by the paraventricular hypothalamus (PVH). However, the distinct roles of oxytocin and its co-transmitters remain unresolved. Using chemogenetics, we showed that activation of PVH oxytocin neurons was sufficient to elicit both responses, whereas silencing these neurons abolished them. Viral tracing revealed that these neurons project collaterally to the brainstem reticular nucleus and spinal cord to spatially coordinate autonomic and somatic motor outputs. By dissecting the molecular mechanisms using CRISPR-Cas9, we found that vesicular glutamate transporter 2 (VGLUT2)-dependent glutamatergic transmission provides the primary drive for both behaviors, whereas the oxytocin peptide is selectively required for yawning but dispensable for erection. Comparative analyses across rats, hamsters, and mice demonstrated that while the glutamatergic erectile circuit was conserved, mice lacked spontaneous yawning and were resistant to apomorphine-induced yawning. These findings suggest a hierarchical co-transmission framework in which fast glutamatergic signaling provides the core drive, while oxytocin confers behavioral specificity.
Functional specialization in the higher visual areas (HVAs) has traditionally been attributed to the segregation of distinct visual features; however, the role of feature integration remains poorly understood. In this study, we investigated the processing of color and motion in the visual cortex by developing a neuronal color-purity assessment strategy. Our results demonstrate that the joint encoding of color purity and motion distinguishes the functional roles of the four HVAs, whereas tuning preferences segregate them into two groups. Specifically, correlations between color purity and motion are area-specific across the HVAs, whereas tuning preferences follow the putative dorsal and ventral streams. The anatomical results suggest that joint encoding in the HVAs may be related to the primary visual cortex neurons with projections to multiple targets. Collectively, these findings reveal that feature integration, operationally defined via joint encoding, provides a finer dimension of functional differentiation than segregation alone, thereby establishing a novel mechanism underlying cortical functional specialization.
Blood-brain barrier (BBB) disruption is a major driver of neurological deficits after intracerebral hemorrhage (ICH); however, its mechanisms remain unclear. Here, we found that TRIM47 was markedly upregulated after ICH and predominantly expressed in endothelial cells. Endothelial-specific Trim47 deletion normalized peri-hematoma vascular remodeling by reducing the abnormal vascular area and diameter and increasing pericyte coverage, thereby preserving BBB integrity, improving perfusion, reducing neuronal death, and enhancing neurological recovery. Mechanistically, TRIM47 binds to cylindromatosis (CYLD) and promotes its ubiquitination and degradation, leading to activation of NF-κB and P38/JNK-MAPK signaling and neurovascular injury. Endothelial CYLD overexpression reproduced the protective effects of Trim47 deficiency, whereas CYLD knockdown abrogated these effects, confirming that CYLD is a key downstream mediator. Importantly, AAV-mediated Trim47 knockdown restored vascular integrity and improved outcomes after ICH. These findings identify endothelial TRIM47 as a potential therapeutic target for BBB repair and neurovascular recovery.
Thermal homeostasis is critical for mammalian physiology. The hypothalamic preoptic area (POA) is a key center for thermoregulation and contains calcium/calmodulin-dependent protein kinase type I (CaMKI)-positive temperature-insensitive neurons, whose functional roles remain unclear. Here, we found that calcium oscillations of CaMKI-positive POA (POACaMKI) neurons decreased during adenosine monophosphate (AMP)-induced hypothermia via the adenosine A1 receptor, with the power spectral density of the delta-band exhibiting a power-scaling law associated with changes in core body temperature (~ΔTcore3). This suggests that POACaMKI neurons encode Tcore reference information via delta-band dynamics. The observed power-law scaling indicated a robust association between POACaMKI neuronal activity and thermoregulatory dynamics, suggesting that these neurons may contribute to both body temperature sensing and control. This study reveals a negative feedback mechanism for thermal homeostasis and provides a paradigm shift for decoding information in the frequency domain and understanding the neural regulation of physiological homeostasis.
Tinnitus is a common refractory disorder with complex mechanisms. Emerging evidence suggests that inflammation plays key roles in tinnitus pathogenesis; however, its overall inflammatory signatures remain underinvestigated. This study integrates transcriptomic data from patients with tinnitus and a noise-induced mouse model to identify conserved neuroinflammatory pathways. RNA sequencing of blood samples from patients with tinnitus and concurrent hearing loss revealed significant enrichment of immune-related pathways. Similar inflammatory signatures were detected through transcriptomic and cytokine profiling of the peripheral blood samples obtained from mice with noise-induced hearing loss. Microglial activation and elevated pro-inflammatory cytokines were observed in the cochlear nucleus and auditory cortex during the onset of noise-induced tinnitus. Pharmacological inhibition of microglial activation or tumor necrosis factor-α signaling alleviated tinnitus-like behaviors in mice. These findings reveal a dynamic peripheral-to-central inflammatory axis in tinnitus as well as identify blood-based biomarkers and auditory-center inflammation as potential therapeutic targets.
Patients with Alzheimer's disease (AD) frequently experience inflammatory insults; however, the mechanisms by which microglia respond to these challenges remain unclear. Although AD microglia have been proposed to be primed for exaggerated inflammatory responses, single-cell evidence remains limited. To investigate microglial responses to inflammation in AD, we challenged AD mouse models with intraperitoneal lipopolysaccharide (LPS) and used single-cell RNA sequencing to characterize microglial states, along with in vivo immunostaining and in vitro models to define their features and underlying mechanisms. We found that, in response to an inflammatory challenge, microglia adopted a low-inflammatory state accompanied by elevated expression of mitochondrial respiratory chain genes. This state was associated with the phagocytosis of dystrophic neurites and was recapitulated in vitro using an efferocytosis-based model, with apolipoprotein E implicated in its underlying mechanism. In summary, we identified a distinct microglial state that provides new insights into the dynamic role of microglia in AD.
The medial prefrontal cortex (mPFC) contains projection-defined neuronal populations that route information to multiple downstream targets. However, their role in reward learning remains unclear. Here, we identified and functionally characterized a subpopulation of mPFC neurons collateralizing to the dorsomedial striatum (DMS) and the contralateral anterior insular cortex (aIC). Fiber photometry and single-cell calcium imaging revealed that mPFCDMS+aIC neurons responded robustly to reward stimuli and exhibited learning-enhanced, unconditioned stimulus (US)-evoked activity during reward conditioning, whereas conditioned stimulus (CS) responses remained stable. This enhancement reflected an increased response magnitude and a greater proportion of US-responsive neurons. Importantly, optogenetic inhibition of these neurons during the US period, but not during the CS period, impaired the acquisition of conditioned anticipatory licking. Taken together, our findings identify a finely projection-defined mPFC neuronal subpopulation that preferentially contributes to reinforcement-related updating during reward learning.
