Although Alzheimer's disease (AD) has a polygenic architecture, with numerous associated single-nucleotide polymorphisms (SNPs) identified, the contribution of structural variants (SVs) is unclear. In this study, using long-read (n = 11) and short-read (n = 3,190) sequencing data from the Chinese population, we show that common SVs contribute to AD heritability beyond common SNPs. We identify an expanded CCG repeat in the FAM193B promoter that shows a genome-wide significant association with increased AD risk (odds ratio = 2.20 per 10-repeat increase, P = 5.5 × 10-13). The expanded FAM193B-CCG repeat increases FAM193B expression and mediates the pleiotropic association between brain FAM193B expression and AD risk. Analyses of postmortem human brains and cultured neuronal cells show that elevated neuronal FAM193B expression is associated with DNA damage and cell death-related pathways. These findings establish the common FAM193B-CCG repeat as an AD risk genetic factor and highlight the contribution of common SVs to AD heritability.

Lysergic acid diethylamide (LSD) is a potent psychedelic with increasing therapeutic interest, yet qualification of target engagement using in vivo neuroimaging has not yet been performed. Using simultaneous positron emission tomography-magnetic resonance imaging technology, we describe multiple brain actions of LSD in seven healthy volunteers blinded to LSD dose received. Here we show that LSD occupies 5-HT2AR with a high affinity and increases both global cerebral blood flow (CBF) and internal carotid artery flow. LSD also decreases global connectivity, which was negatively associated with changes in CBF. We observe an anticlockwise hysteresis loop between plasma drug levels and subjective effects, suggesting atypical pharmacodynamic mechanisms. We contrast our CBF and global connectivity findings and their relation in a separate cohort of 25 participants administered psilocybin, highlighting key consistencies and differences. By establishing the dose-occupancy relation of LSD in humans, our findings provide insights for the clinical development of psychedelic compounds and demonstrate unique neurophysiological effects that distinguish LSD from psilocybin.

Although it is commonly assumed that early blind individuals have enhanced pitch perception, the literature to date has been contradictory. We measured performance on two tasks known to recruit early versus late stages of auditory frequency tuning in early blind and sighted human adults of both sexes with matched years of musical training. The two groups showed equivalent performance on a tone detection in notched-noise task that assesses cochlear frequency selectivity. In contrast, early blind individuals showed enhanced performance in a pitch discrimination task thought to be mediated by cortical mechanisms. Computational modeling revealed that this enhancement was best explained by reduced internal noise rather than narrower frequency tuning, with both blindness and years of musical training predicting a reduction in internal noise. These findings identify internal noise as a key factor in experience-driven auditory plasticity as a result of both musical experience and early blindness.Significance Statement For centuries, early blindness has been associated with superior auditory abilities. Here we find that the enhanced pitch perception in early blind individuals is best explained by reduced internal noise at higher levels of auditory processing, rather than sharper frequency tuning. Years of musical training similarly resulted in lower internal noise, suggesting a shared mechanism through which experience improves auditory perception. These findings identify internal noise reduction as a key component of experience-dependent auditory plasticity.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder of complex etiology with substantial genetic contribution. Oxidative stress and GABAergic dysregulation are implicated in the pathophysiology of ASD. Both genetic variations in NEF2L2 (Nuclear factor (erythroid-derived 2)-like 2, an antioxidant regulator) and GABRB3 (GABRB3 encodes the GABA-A receptor β3 subunit) may increase susceptibility to ASD. This is the first study of the two genes in this field in the context of the Iraqi children. Because the NEF2L2 control genotype distribution deviated significantly from Hardy-Weinberg equilibrium (χ2 = 50.05, P < 0.0001), the NEF2L2 CT-genotype association below is reported as provisional pending independent genotyping verification; stratified subgroup findings are reported after Benjamini-Hochberg false-discovery-rate correction.This case-control study engaged 90 Iraqi children. Both GABRB3 rs2081648 and NEF2L2 rs35652124 polymorphisms were genotyped using Tetra-ARMS-PCR. GABA and NRF2 were also evaluated both using serum and protein, involved in elements of the oxidative stress, and biomarkers were analyzed. This study also conducted both a haplotype and an epistatic analysis. In exploratory analysis, the NEF2L2 rs35652124 CT genotype showed an apparent association with increased ASD risk; however, because the NEF2L2 control genotype distribution deviated severely from Hardy-Weinberg equilibrium, this association is provisional and is not treated as a confirmed finding of this study. The GABRB3 rs2081648 CT genotype presented robust evidence of protection. The ASD group was found to have a significant decrease in both GABRB3 (43.8%) and NRF2 (43.7%) proteins. The combined biomarker panel for the ASD population was AUC = 0.834. The T-C haplotype presented the most pronounced risk (OR = 2.84, P = 0.003; FDR q = 0.012). The two-locus epistatic interaction (P = 0.028, based on 1,000 permutations) is preliminary pending a confirmatory 10,000-permutation analysis. The GABRB3 polymorphism and serum GABRB3/NRF2 biomarkers are associated with GABA-mediated impairments in ASD in Iraqi children; the NEF2L2 CT-genotype association remains exploratory pending independent genotyping verification.

We evaluated the effects of 2-mA and 4-mA anodal transcranial direct current stimulation (tDCS), targeting the left dorsolateral prefrontal cortex (DLPFC), on endurance performance, prefrontal head oxygenation, cognition, and psychophysiological responses in trained cyclists. Eighteen trained male cyclists (age: 36.0 ± 8.52 years; V̇O2max: 58.82 ± 8.16 ml·kg-1·min-1) performed 20-km time trials (TT) after receiving 20-min 2 mA, 4 mA, or sham tDCS in a randomized, double-blind, crossover design. Head oxyhemoglobin (HbO2) and deoxyhemoglobin (Hbb), and cognitive performance (Stroop test) were assessed pre-tDCS, post-tDCS, and post-TT. Power output, heart rate (HR), and HbO2/Hbb were also monitored, with ratings of perceived exertion (RPE) and affective response collected during TT. The intervention was well-tolerated with successful blinding. Relative to sham, 2 mA increased average power and reduced completion time, with no difference from 4 mA; it also raised HR above both sham and 4 mA. During exercise, 2 mA raised left-hemisphere HbO2 relative to 4 mA and Hbb relative to both sham and 4 mA. The 2-mA power gain was greater with slower baseline reaction time. No condition affected cognition, RPE, or affective responses. A single session of 2 mA anodal tDCS produced small, practically relevant improvements in endurance performance relative to sham alongside intensity-dependent changes in prefrontal head oxygenation, with the largest performance benefit associated with poorer baseline cognitive performance; 4 mA did not differ from sham on either outcome. These findings suggest a non-monotonic intensity-response relationship, where higher intensity does not necessarily produce a larger effect.

Cerebral motor areas, such as the primary motor cortex (M1), premotor cortex (PM), and supplementary motor area, are rhythmically activated within the gait cycle, and transcranial alternating current stimulation (tACS) at the gait cycle frequency over the M1 entrains gait rhythm and improves gait variability. However, whether altering the tACS frequencies to be slower or faster than the normal gait cycle frequency changes and improves gait rhythms remains unclear. Therefore, we investigated the effects of different tACS frequencies around the gait cycle frequency over the C1 and C2 targeting the M1 (Experiment 1) and over the FC3 and FC4 targeting the PM (Experiment 2) on spatiotemporal gait parameters in 30 healthy young adults. Each experiment involved treadmill gait measurements with 5-min tACS at the following four conditions: normal gait cycle frequency (100% rhythm), slower and faster gait cycle frequencies (90% and 110% rhythms, respectively), and sham stimulation. Spatiotemporal gait parameters (gait cycle time, stance time, swing time, and stride length) were measured using optical sensors for each tACS condition. Gait-combined tACS over the M1 in the 110% rhythm frequency significantly decreased the change in coefficient of variation (CV) of swing time compared with the 90% rhythm frequency and sham stimulation. Furthermore, gait-combined tACS over the PM in the 100% rhythm frequency significantly decreased the change in CV of stride length compared with the sham stimulation. Therefore, gait-combined tACS at natural or faster frequencies than the normal gait cycle frequency over the cerebral motor areas decreased the spatiotemporal gait variabilities.

Cellular senescence, characterized as a permanent arrest of cell proliferation, is triggered by various types of stress. Senescent cells are identified by markers, including senescence-associated β-galactosidase (SA-β-gal) activity and the secretion of senescence-associated secretory phenotype (SASP) factors. These senescent phenotypes have been observed in neurons, suggesting that cellular senescence may contribute to the pathogenesis of neurodegenerative diseases. Humanin (HN), an endogenous short peptide, mitigates Alzheimer's disease-associated pathologies, including amyloid β-induced neuronal cell death. Overexpression of HN extends the lifespan of nematodes, suggesting a potential anti-aging role for this peptide. Here, we first investigated the effect of HN on cellular senescence in mouse primary cortical neurons. Chronic treatment with HNG, a highly potent HN derivative, attenuated prolonged culture-induced senescence. To further determine whether this anti-senescent effect is associated with preserved exocytotic function, we employed a glutamate-induced senescence model in neuronal-differentiated PC12 cells. In this system, HNG mitigated changes in senescence-associated markers, including increases in SA-β-gal activity, Ki67 expression, and SASP factor expression. In addition, acetylcholine-induced dopamine release was reduced in senescent PC12 cells, whereas chronic HN treatment sustained the expression levels of synapsin 1 and synaptophysin and attenuated the senescence-associated decrease in neurotransmitter release. These findings suggest that HN suppresses senescence and sustains exocytosis activity in neuronal cells, supporting an anti-aging function of HN at the cellular level.

Understanding how network structure shapes neural population dynamics and representation of external inputs is a key issue in neuroscience. This study proposes a modeling framework for recurrent spiking neural networks (RSNN) and elucidates dynamical computation mechanism of RSNN by linking input dimensionality, network structure and dynamic representation. Inspired by biological neural systems, the RSNN leverages the low-rank connectivity and small-world topology for robust dynamics and efficient computation. The proposed framework is applied in behavior and recognition tasks with multiscale inputs to evaluate the representation capability of RSNN. It is found that neural computation is accomplished by high-dimensional network responses to external inputs, that can be represented by nonlinear dynamics embedded in low-dimensional manifolds. Based on computational and dynamical analysis, we show that high-dimensional neural activity can be decomposed into a steady-state component and a transient component residing in the orthogonal subspace. The steady-state component is jointly regulated by network connectivity vector and input vector, whereas the transient component is determined by topological structure. Interestingly, representation reliability is optimized when the rank of RSNN is aligned with the intrinsic dimensionality of the external input. Compared with regular and random networks, small-world topology of RSNN can largely improve the accuracy of dynamic representations. This work provides a guidance for designing brain-inspired network models with optimized structures and dynamics for efficient computation.

Alternative polyadenylation (APA) regulates transcript 3'-end architecture, stability, localization, and translation. Although RNA-binding protein dysfunction is central to amyotrophic lateral sclerosis (ALS), whether different ALS-associated proteins cause shared APA abnormalities remains unclear. We analyzed poly(A)-site usage after TDP-43 knockdown, TDP-43 K263E expression, FUS knockout, FUS P525L expression, and MATR3 knockout. Using false-discovery rate (FDR) < 0.05 as the primary criterion, evidence varied markedly among datasets. FUS knockout produced the strongest response, with 373 significant events affecting 239 genes. Three events involving two genes remained significant after TDP-43 knockdown, and two events involving one gene remained significant in the TDP-43 K263E dataset. No events survived FDR correction after FUS P525L expression or MATR3 knockout, and no FDR-significant events or genes were shared between datasets. We therefore examined nominal events (unadjusted P < 0.05) as an explicitly exploratory layer. Nominal event overlap was enriched in 7 of 10 pairwise comparisons, and nominal gene overlap in 9 of 10. TDP-43 knockdown and TDP-43 K263E showed the strongest directional agreement: 65 nominal events were shared; 25 were directionally classified in both datasets, of which 23 were concordant. FUS knockout and FUS P525L also showed enriched nominal overlap, but without significant directional concordance or correlated ΔPAU responses. Thus, FUS loss induces a robust FDR-supported APA phenotype, whereas evidence is substantially weaker in other contexts. Cross-dataset similarities occur mainly among exploratory nominal targets and do not consistently extend to direction or magnitude. APA responses therefore show partial, context-dependent convergence rather than a universal defect.

Rhythmic sensory stimulation modulates oscillations via frequency-specific entrainment, but synchronized auditory contributions remain unclear, and periodic-aperiodic decomposition has not been applied to audiovisual entrainment. Forty adults received visual stimulation at 8, 20, and 40 Hz, alone (VF) or synchronized with binaural beats of identical frequencies (VF + BB). EEG was analyzed using power spectral density (PSD), topographical mapping, Sample Entropy (SampEn), Lempel-Ziv Complexity (LZC), Phase-Locking Regularity (PLR), and IRASA to separate periodic (SSVEP) from aperiodic (1/f) contributions. Visual flicker induced frequency-specific entrainment, and binaural beats modulated responses frequency-dependently. At 8 Hz, flicker elicited a periodic SSVEP; adding binaural beats enhanced this component and increased aperiodic activity. At 20 Hz, synchronized audiovisual stimulation enhanced both periodic and aperiodic components. At 40 Hz, IRASA showed no significant periodic modulation; VF + BB produced a widespread increase in aperiodic offset and exponent, absent under VF alone. VF + BB reduced SampEn across all frequencies and increased PLR at 8 and 20 Hz, whereas LZC decreased at 8 Hz and increased at 20 Hz. Synchronized audiovisual stimulation produced frequency-dependent changes in EEG spectral organization. At 8 and 20 Hz, adding binaural beats enhanced the periodic SSVEP component, with changes in the aperiodic background. At 40 Hz, conventional PSD showed increased gamma activity, but periodic-aperiodic decomposition did not reveal significant periodic enhancement; audiovisual stimulation primarily altered aperiodic offset and exponent. Complementary regularity and phase-based measures showed frequency-dependent temporal changes. Findings highlight combining conventional spectral analysis, periodic-aperiodic decomposition, and complementary EEG biomarkers to characterize synchronized audiovisual stimulation.

Although 17β-estradiol (E2) is a critical neuromodulator of hippocampus-dependent memory and synaptic plasticity, the molecular mechanisms underlying these effects remain incompletely understood. Previous studies showed that E2 enhances dorsal hippocampus-dependent memory consolidation by activating signaling pathways that promote protein synthesis and dendritic spine formation. However, these studies largely overlooked the contribution of protein degradation mediated by the ubiquitin proteasome system (UPS), despite extensive evidence implicating UPS activity in long-term memory and synaptic plasticity. Here, we combined temporally specific dorsal hippocampal infusions of the proteasome inhibitor β-lactone with three-dimensional spine morphometry to examine the role of UPS-mediated protein degradation in E2-induced memory consolidation and CA1 spinogenesis. Immediate post-training bilateral infusion of β-lactone into the dorsal hippocampus of ovariectomized female mice blocked E2-induced enhancement of object recognition memory and attenuated E2-associated improvements in spatial memory. Arbor-wide Golgi-based analyses revealed robust E2-induced increases in spine number across the apical dendritic tree and smaller parallel effects within the basal arbor. Segment-level analyses showed that E2 produced the greatest structural changes on tertiary apical dendritic segments, increasing total, mushroom, and thin spine density and enhancing multiple morphometric features, including mushroom spine surface area and head-to-neck ratio. Secondary basal dendritic segments exhibited smaller, more variable changes. Many E2-associated structural effects were attenuated or abolished by β-lactone. Together, these findings provide the first evidence that proteasomal protein degradation contributes to estrogenic enhancement of hippocampus-dependent memory and CA1 dendritic spine remodeling, identifying UPS-mediated protein degradation as a previously unrecognized mechanism regulating estrogenic memory consolidation and structural plasticity.Significance Statement 17β-estradiol (E2) rapidly enhances hippocampal memory consolidation and promotes CA1 dendritic spinogenesis, yet the molecular mechanisms that support these effects remain unclear. Here, we combine temporally specific dorsal hippocampal proteasome inhibition with three-dimensional Golgi-based spine analyses to show that proteasomal protein degradation is required for E2-induced enhancement of object recognition memory and contributes to E2-associated improvements in spatial memory in ovariectomized female mice. We further demonstrate that proteasome activity contributes to E2-induced increases in apical CA1 spine density and morphology. These findings reveal new insights into estrogenic modulation of cognition that may provide novel protein targets whose levels could be regulated to reduce memory dysfunction related to menopause, depression, and other conditions for which women are at greater risk.

The aperiodic, 1/f-like component of electrophysiological activity is increasingly recognized as a meaningful feature of neural function rather than background noise. Meanwhile, many EEG studies interpret transient post-stimulus changes in oscillatory power as signatures of attention, salience, or cognitive control. Such interpretations typically depend on baseline normalization, which assumes aperiodic activity remains stable from pre- to post-stimulus periods. Using high-density EEG from typically developing children, we tested this assumption across two paradigms: an audiovisual simple reaction-time task (n = 36, 19 males and 17 females) and a visual oddball task (n = 38, 20 males and 18 females). In each, conventional spectral analyses were compared with analyses that explicitly modeled and removed aperiodic activity in both windows. Across tasks, stimulus onset produced robust increases in aperiodic exponent and offset, indicating systematic 1/f changes. In the audiovisual task these were modality-specific, with central, parieto-occipital, or combined topographies by stimulus type. They diminished but persisted after ERP removal, suggesting they were not fully explained by phase-locked activity. Critically, once aperiodic activity was accounted for, the apparent theta increase was largely abolished in both tasks, including the canonical fronto-central enhancement to infrequent targets. The conventional method also overestimated beta desynchronization, especially in the induced signal, indicating a spurious consequence of spectral slope steepening. By contrast, alpha desynchronization remained robust and was enhanced, reflecting genuine suppression. Together, these findings suggest many conventional time-frequency effects, particularly apparent theta synchronization, may reflect stimulus-driven aperiodic changes rather than robust narrowband changes, challenging core assumptions of these analyses.Significance statement Frequency-domain neural activity comprises both narrowband oscillations and broadband aperiodic activity. Conventional time-frequency analyses use baseline normalization to isolate oscillatory responses, implicitly assuming that aperiodic activity remains stable following stimulus onset. Across two EEG paradigms, we show that stimulus presentation systematically alters aperiodic activity in a sensory- and attention-dependent manner. These changes can produce apparent increases in theta-band power that do not reflect genuine narrowband oscillations and can exaggerate beta desynchronization. In contrast, alpha desynchronization remained robust after accounting for aperiodic activity. These findings demonstrate that stimulus-related aperiodic changes can substantially influence conventional time-frequency measures and should be explicitly considered when interpreting post-stimulus oscillatory responses.

Competitive stimulus interactions across the space map of the midbrain superior colliculus (SC) are critical for spatial decision-making among multiple options. Here, using electrophysiological recordings from the intermediate and deep layers of the SC (SCid) in mice of either sex, we discovered that the rules and spatial profiles of these competitive interactions are different between local within-receptive field (RF), versus global across-RF-boundary, spatial scales. When one visual stimulus was centered in the RF and a second one was located within the RF's classical inhibitory surround, we found that stimulus interactions followed an averaging rule. This classical surround was spatially restricted, and the strength of inhibition underlying these within-RF interactions decreased with distance from the RF center. By contrast, when the second stimulus was located outside the RF, stimulus interactions followed a divisive rule. Strikingly, this extra-classical inhibitory surround was spatially global, and the strength of competitive inhibition underlying these across-RF-boundary interactions was distance-invariant while being dependent on the relative strengths of the competing stimuli. Computational modeling revealed that whereas within-RF interactions are well-explained by a normalization-like mechanism driven by pooled inhibition, across-RF-boundary interactions are not, and instead, are well-explained by a winner-take-all-like mechanism driven by structured, donut-like inhibition. Combined, our results reveal the mechanistic logic of stimulus competition across the space-map of mammalian SCid.Significance statement Selecting one target among many is essential for diverse cognitive functions, and requires neural circuits to compare priorities of competing stimuli. Using electrophysiological recordings in the mouse superior colliculus, a critical brain area for spatial decision-making, we show that stimulus competition follows fundamentally different rules at local versus distant spatial scales. Nearby stimuli within a receptive field (RF) engage spatially restricted, decaying inhibition, enacting an averaging rule. By contrast, distant stimuli separated by the RF boundary engage spatially global, distance-invariant inhibition, enacting a divisive, relative strength-dependent rule. Computational modeling reveals that local interactions are explained by a pooling normalization mechanism, whereas global interactions are explained by a donut-like winner-take-all mechanism. Results resolve long open questions about stimulus competition in the SC.

The central melanocortin system is crucial for controlling food intake and metabolism. It includes neurons that produce pro-opiomelanocortin (POMC), a prohormone that generates the melanocortin receptor (MCR) agonist alpha-melanocyte-stimulating hormone (α-MSH), and neurons that produce agouti-related protein (AgRP), an endogenous MCR antagonist. This system also influences neuroendocrine neurons, thereby impacting pituitary hormone secretion. However, it remains unclear whether the central melanocortin system also modulates growth hormone (GH) secretion. Here we showed that arcuate nucleus (ARH) GH-releasing hormone (GHRH) neurons receive inputs from α-MSH and AgRP axons. α-MSH activates a subset (∼25%) of ARH[GHRH] neurons. Serial blood GH measurements were taken before and after systemic saline or clozapine N-oxide injections in mice expressing the excitatory hM3Dq-Gq receptor in POMC-expressing cells. Activation of POMC-expressing cells elevated blood GH levels compared with baseline or saline-injected mice, in both males and females. To determine whether AgRP neurons inhibit GH secretion, mice expressing the hM3Dq-Gq receptor simultaneously in AgRP- and GHRH-expressing cells were created. While chemogenetic activation of GHRH neurons caused a strong GH secretion, co-activation of AgRP neurons inhibited this response in both sexes. Additionally, Fos expression in GHRH-activated neurons was blunted when AgRP neurons were co-stimulated. Mice expressing the hM3Dq-Gq receptor only in MC4R-expressing cells were also investigated; however, activation of MC4R neurons did not alter GH levels. In conclusion, the central melanocortin system modulates the activity of GHRH neurons and GH secretion possibly through MC4R-independent pathways. These findings highlight a critical hypothalamic neurocircuit that integrates metabolic cues to regulate the somatotropic axis.Significance Statement The central melanocortin system processes both short- and long-term nutritional signals to regulate metabolism and various neuroendocrine axes. Here, we show that growth hormone (GH) secretion is controlled by hypothalamic neurons of the central melanocortin system, including populations that express POMC and AgRP. This regulation occurs, at least in part, through modulation of GH-releasing hormone neuron activity, a key group of cells that control pituitary GH secretion. Overall, these findings reveal a hypothalamic circuit that links nutritional status to the regulation of the GH axis, providing new insights into how growth is adaptively controlled by energy availability.