NOTCH2NLC-related neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder with marked clinical heterogeneity and an increasingly recognized phenotypic spectrum. Although hydrocephalus-like presentations, i.e. ventriculomegaly with concomitant with cognition, motor, and/or bladder dysfunctions, have been observed in NIID sporadically, their prevalence, clinicopathological characteristics, and potential clinical implications remain poorly understood. This retrospective cohort study systematically characterized this newly recognized hydrocephalus-like phenotype. We conducted an MRI-based screening to identify previously undiagnosed NIID cases from a cohort of 498 adults with imaging diagnosis of communicating hydrocephalus. Four such cases were identified and incorporated into our NIID cohort, with genetic and pathological confirmation. A total of 68 NIID patients were analyzed, of whom 19 (27.9

OBJECTIVE:Epilepsy is a common neurological disorder characterized by recurrent seizures, often resulting from an imbalance between neuronal excitation and inhibition. Loss of cerebellar Purkinje cells (PCs) has been observed in some patients with chronic epilepsy; however, whether PC loss can initiate seizures or exacerbate seizure severity remains unclear. METHODS:We established a mouse model of selective PC ablation in adulthood using the diphtheria toxin (DT)/DT receptor (DTR) system. Seizure susceptibility (epileptiform discharges, Racine score, and network activation) was assessed thoroughly in two distinct seizure models: the pentylenetetrazol (P-uced acute seizure model and the hippocampal kindling model. Furthermore, in vivo electrophysiology recordings in the deep cerebellar nuclei (DCN) were utilized to explore the single-unit firing characteristics following PC ablation. RESULTS:One month after intraperitoneal (i.p.) DT injection, PC ablation was successfully induced in adult Pcp2-DTR mice. No spontaneous seizures were observed in mice with PC ablation during 48-h wireless electroencephalography/electromyography (EEG/EMG) monitoring. However, PC ablation significantly increased seizure susceptibility in the PTZ-induced acute seizure model and accelerated the kindling process in the hippocampal kindling model. Although baseline DCN firing remained unchanged, these mice displayed a distinct post-ictal DCN electrophysiological signature: significantly enhanced delta/theta power compared to controls, and a decrease in neuronal firing frequency relative to their own baseline, with firing regularity preserved. SIGNIFICANCE:Together, these findings suggest that PC ablation contributes to heightened seizure susceptibility and seizure severity, highlighting a modulatory role of cerebellar circuits in epilepsy.

For decades, prevailing models of psychosis-including schizophrenia and various neurodegenerative disorders have largely interpreted hallucinations and delusions through the lens of neurodegeneration and neurotransmitter imbalance. In this view, psychotic symptoms emerge as the consequence of progressive and largely irreversible neural decline. Yet, an alternative picture has begun to emerge from accumulating evidence. Rather than reflecting only loss, psychosis in a subset of cases may represent a fundamentally different developmental trajectory one that resembles a re-emergence of early, highly plastic brain states. We refer to this hypothesis as “pathological neoteny,” in which the brain appears, in certain respects, to revert toward immature modes of cognition characterized by heightened plasticity and reduced constraints on internal representations. Intriguingly, many phenomenological features of psychosis-such as vivid internal imagery, weakened boundaries between perception and imagination and intensified associative thinking echo aspects of normative childhood cognition. However, while these similarities are striking, the underlying mechanisms remain poorly understood and the boundary between developmental plasticity and clinical pathology remains unclear. In this Perspective, we bring together emerging neuroimaging and molecular evidence that points toward atypical developmental timing, including delayed maturation and sustained plasticity in specific psychotic subgroups. We situate these findings against established frameworks in developmental neuroscience, particularly synaptic pruning, critical period closure and the adaptive advantages of childhood neural flexibility. Importantly, we emphasize that psychosis is heterogeneous: not all cases can be explained within a single framework. We therefore highlight the need to carefully distinguish normative childhood imagination from pathological states, while also acknowledging the conceptual, methodological and ethical challenges inherent in this distinction. Looking forward, we propose a research agenda centered on longitudinal, multi-modal developmental comparisons, biologically grounded subgroup stratification and mechanistic mapping of how plasticity itself might become dysregulated. Such work also raises translational questions both promising and cautionary-regarding whether and how brain plasticity could be therapeutically modulated. Taken together, this re-evaluation challenges the long-standing assumption that psychosis is solely a story of decline, instead suggesting a more nuanced narrative in which altered developmental timing and plasticity may play a central role in shaping mental experience and its disorders.

Background Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder, with neuroinflammation believed to be a key driver. PET radioligands targeting the 18-kDa translocator protein (TSPO) serve as in vivo markers of neuroinflammation. This study aimed to evaluate TSPO-PET in assessing neuroinflammation severity in NIID and to investigate its relationship with clinical features, using [¹¹C]-ER176 and [¹⁸F]-FDG PET/MR in ten NIID patients and five epilepsy controls. Results TSPO-PET standard uptake value ratios (SUVR) were significantly elevated in NIID patients compared to controls, regardless of brain template used (p < 0.01). TSPO-PET SUVR of superficial white matter was negatively correlated with fractional anisotropy (R = -0.817, p < 0.05). No significant differences in SUVR were found among NIID subgroups based on modified Rankin scale score ≥ 4, NOTCH2NLC GGC repeats ≥ 110, onset age, or encephalitis syndrome. Conclusions This study demonstrates that increased neuroinflammation is closely linked to white matter fiber damage. These findings highlight the role of inflammation in NIID pathophysiology and suggest TSPO-PET as a valuable tool for monitoring disease progression.

Objectives Neuronal intranuclear inclusion disease (NIID) is a multisystem neurodegenerative disorder caused by GGC repeat expansions in the NOTCH2NLC gene. Although genetic testing has improved diagnostic efficiency, histopathologic confirmation remains essential. We investigated whether routine archival surgical specimens could serve as an alternative pathologic resource for NIID diagnosis.Methods We retrospectively analyzed archival formalin-fixed, paraffin-embedded specimens from patients with genetically confirmed NIID, including gastric antrum, colon, gallbladder, prostate, and kidney tissues. Hematoxylin-eosin staining and immunofluorescence for p62 and uN2CpolyG were performed to identify characteristic intranuclear inclusions. Histopathologic evaluation was conducted in a blinded manner and compared with non-neurologic control tissues.Results Characteristic eosinophilic intranuclear inclusions positive for p62 and uN2CpolyG were detected in all NIID archival specimens but not in control tissues. These inclusions were consistently identified across gastrointestinal and urogenital tissues, including small endoscopic biopsy samples. Ultrastructural examination further demonstrated dense filamentous intranuclear material in gastric tissue. Notably, inclusions were preferentially localized to fibroblasts and smooth muscle cells within the lamina propria and muscularis mucosae, whereas epithelial cells were consistently spared. Detection was not apparently affected by tissue type or storage duration.Conclusions Routine archival surgical specimens may provide a readily available pathologic resource that avoids additional invasive biopsy for confirming NIID. Their consistent cellular distribution pattern may also facilitate recognition of diagnostic inclusions in routine pathology practice.

BACKGROUND AND PURPOSE:Efgartigimod, a neonatal Fc receptor inhibitor, reduces IgG recycling and thus decreases pathogenic IgG autoantibody levels. This subpopulation analysis aimed to assess the efficacy, safety, and tolerability of subcutaneous efgartigimod PH20 in Chinese participants with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS:ADHERE was a multistage, randomised-withdrawal, placebo-controlled phase II trial in adult participants with active CIDP. Eligible participants received open-label treatment with efgartigimod weekly for ≤12 weeks (Stage A) and those with confirmed evidence of clinical improvement (ECI) were randomised to receive double-blind treatment with efgartigimod or placebo weekly for ≤48 weeks (Stage B). Primary endpoints were proportion of participants with confirmed ECI (Stage A) and time to clinical deterioration as measured by adjusted Inflammatory Neuropathy Cause and Treatment score (Stage B). This descriptive analysis reports the results from the Chinese subpopulation. RESULTS:ADHERE enrolled 58 participants from mainland China for Stage A and of those, 47 were randomised (21 efgartigimod, 26 placebo) for Stage B. In Stage A, 45 (77.6%; 95% confidence interval [CI], 64.7%-87.5%) participants achieved confirmed ECI. In Stage B, median time to clinical deterioration was not reached with efgartigimod vs. 113.0 days (95% CI, 43.0-181.0 days) with placebo (hazard ratio, 0.313; 95% CI, 0.109-0.905). Across stages, most adverse events were mild or moderate, and no death occurred. No adverse events led to treatment discontinuation. CONCLUSIONS:Subcutaneous efgartigimod PH20 demonstrated clinical response and lowered the risk of clinical deterioration compared to placebo in Chinese participants with CIDP, while maintaining favourable safety and tolerability profiles.

BACKGROUND:Epoxyeicosatrienoic acids (EETs) are bioactive lipid mediators derived from arachidonic acid (ARA) via cytochrome P450 (CYP450) enzymes. They exert pleiotropic effects including anti-inflammation, anti-apoptosis, antioxidant activity, and vasodilation. Soluble epoxide hydrolase (sEH) rapidly hydrolyzes EETs to inactive diols, and its inhibition has emerged as a promising strategy to potentiate EET-mediated benefits. This review synthesizes current evidence on the roles and mechanisms of EETs and sEH in major neurological disorders and discusses translational challenges and future directions. METHODS:A narrative review was conducted to synthesize evidence on the biosynthesis and metabolism of EETs, the expression and regulation of brain cytochrome P450 epoxygenases and sEH, the neuroprotective effects of EETs, and the therapeutic potential of sEH inhibitors, and to identify current limitations and future strategies for sEH-targeted therapies. RESULTS:EETs ameliorate multiple neurological disorders through anti-inflammatory and anti-apoptotic effects, increased cerebral blood flow, reduced excitotoxicity, decreased dendritic spine loss, reduced oxidative stress, and enhanced neurosteroid secretion. In animal models, sEH inhibition elevates endogenous EET bioavailability, slows progression of various central nervous system diseases, and attenuates brain injury. However, sEH inhibitor development faces several challenges, including species differences in CYP expression, insufficient blood-brain barrier penetration, bleeding risks, failure of some candidates in late-stage trials, and the limitations of single-target inhibition. CONCLUSIONS:EETs are endogenous multifaceted neuroprotective mediators that act through convergent anti-inflammatory, anti-apoptotic, and vascular mechanisms. sEH inhibition represents a highly attractive yet challenging therapeutic strategy for a wide spectrum of central nervous system disorders. Future progress requires: development of brain-penetrant or dual-target sEH inhibitors; identification of EET-specific G protein-coupled receptors (GPCRs) and biomarkers for patient stratification; improved preclinical models that better translate to humans; and rigorous clinical evaluation to define safety and efficacy.

Pyroptosis is an inflammatory type of programmed cell death that may contribute to epilepsy initiation and progression through neuroinflammation. Fatty acid binding protein 5 (FABP5), a lipid chaperone, has been implicated in chronic inflammation. However, whether FABP5 regulates pyroptosis and its pathological role in epilepsy remains uncharacterized. Here, FABP5 was upregulated in astrocytes from temporal lobe epilepsy (TLE) patients, epileptic mice, and primary cells. Deletion of astrocytic Fabp5 significantly attenuated pyroptosis, neuronal loss, and seizure activity in epilepsy. Furthermore, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway was identified as the downstream signaling of FABP5 by RNA sequencing analysis. Mechanistically, Fabp5 knockdown reduced lipid overload, alleviated mitochondrial dysfunction, and suppressed cGAS-STING activation. Pharmacological inhibition of mitochondrial fatty acid import recapitulated these protective effects. In contrast, Sting overexpression abolished the reduced pyroptosis level by Fabp5 knockdown, whereas STING inhibition using C-176 attenuated pyroptosis and seizure activity. Collectively, these findings revealed the regulatory role of FABP5-cGAS-STING-pyroptosis axis in the progression of epilepsy and highlighted the promising potential of astrocytic FABP5 as a therapeutic target for epilepsy.

IntroductionCognitive impairment ties to neurovascular coupling (NVC) dysfunction, which may interact with the glymphatic pathway. This study examined the relationships between NVC, glymphatic clearance, and cognitive function in asymptomatic cerebral small vessel disease (CSVD).MethodsIn 231 asymptomatic CSVD patients, whole-brain NVC was assessed via voxel-wise ratios of cerebral blood flow to fractional amplitude of low-frequency fluctuations (CBF/fALFF) and spatial correlation; glymphatic function via the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index. Partial correlation, linear regression (with covariates), and mediation analyses were used to explore associations with cognitive function.ResultsCBF/fALFF ratio in precuneus and bilateral angular gyrus linked to DTI-ALPS index. Precuneus CBF/fALFF ratio correlated positively with episodic memory; CBF/fALFF correlation coefficients associated with executive function. DTI-ALPS index mediated the latter association (adjusted for demographics, vascular risks, and CSVD neuroimaging markers).DiscussionNVC may be a potential biomarker for cognitive dysfunction in asymptomatic CSVD. Optimizing NVC and glymphatic function could help prevent cognitive impairment in asymptomatic CSVD.

ABSTRACT Polyglycine (polyG) proteins translated from expanded GGC trinucleotide repeats are implicated in a growing group of neuromuscular degenerative disorders characterized by intranuclear inclusions, yet the pathogenic importance of aggregate localization and the mechanisms underlying polyG-induced neurodegeneration remain unclear. Here we show that intranuclear polyG aggregates are markedly more pathogenic than cytoplasmic aggregates in cellular and mouse models. Intranuclear aggregation causes greater cell death, more severe behavioral deficits and neuropathology, and earlier mortality. Mechanistically, intranuclear polyG aggregates impair nascent RNA synthesis and are associated with a transcriptionally repressive chromatin state marked by globally reduced chromatin accessibility, decreased H3K27 acetylation, and increased HDAC3 expression across cellular, mouse, and human disease tissue. Using a light-inducible system, we further show that this transcriptional impairment depends on insoluble intranuclear aggregate formation rather than diffuse polyG alone. Pharmacological HDAC inhibition partially restores histone acetylation and transcriptional output and ameliorates behavioral and pathological abnormalities. Together, these findings identify intranuclear polyG aggregates as the more pathologically relevant species and uncover epigenetic repression of chromatin accessibility and transcription as a potentially common mechanism underlying polyG diseases.

OBJECTIVE:Epilepsy is one of the neurological disorders, characterized by recurrent, spontaneous seizures arising from neuronal hyperexcitability and hypersynchrony in the brain. The mechanisms of epilepsy are intricate and remain elusive. FKBP5 has emerged as a significant protein implicated in neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to investigate the role of FKBP5 in a kainic acid (KA)-induced intrahippocampal epilepsy model and assessed how FKBP5 gain-of-function and FKBP51 inhibition influence neurotransmitter dynamics and neuronal excitability. METHODS:We examined the expression of FKBP5 in the hippocampus of the kainic acid (KA)-induced epilepsy model. To explore the impact of FKBP5 on neuronal activity, we overexpressed FKBP5 in primary cortical neurons and astrocytes, assessing extracellular glutamate levels in neuron-astrocytes co-cultures with or without the FKBP51-selective inhibitor SAFit2 (250 nM). Intrinsic excitability, voltage-gated Na+ currents, and network activity were evaluated using whole-cell patch-clamp recordings and high-density microelectrode arrays (HD-MEAs). RESULTS:We observed an elevated level of FKBP5 in the hippocampus of a kainic acid (KA)-induced chronic epilepsy mouse model, whereas cortical FKBP5 did not show clear changes across the examined post-insult time points.. Moreover, FKBP5 overexpression induced a remarkable increase in the extracellular glutamate level in co-cultured primary cortical neurons and astrocytes. Intriguingly, FKBP5 overexpression modifies the electrophysiological properties of primary neurons, resulting in increased intrinsic excitability and enhanced Na+ currents. Additionally, the network activity exhibits hyperexcitability with FKBP5 overexpression. Notably, SAFit2 treatment was also associated with elevated extracellular glutamate in the co-culture system, while intracellular FKBP5 and EAAT2 protein levels showed no significant group differences in the current dataset. CONCLUSION:These findings suggested that FKBP5 played a significant role in regulating neuronal excitability and extracellular glutamate homeostasis. However, due to discrete sampling and the lack of continuous seizure monitoring, the present in vivo data do not establish a definitive causal contribution of FKBP5 to epileptogenesis, warranting future studies integrating longitudinal EEG and cell-type-specific manipulations.

To investigate gray matter abnormalities in idiopathic generalized epilepsy (IGE) patients using double inversion recovery (DIR) sequence combined with statistical parametric mapping (SPM). We included a total of 31 IGE patients and 31 healthy controls. All participants underwent 3.0T MRI scans of T1WI, T2WI, FLAIR and DIR sequences. In the IGE group, seizure frequency, severity and electroencephalograph performance were recorded in IGE group. Gray matter intensity was analyzed using statistical parametric mapping through individual and group post-processing procedure of DIR images. Spearman analysis and multiple regression analysis were applied for further analysis of clinical factors and regions exhibiting abnormal gray matter intensity. The individual SPM analysis of DIR images revealed gray matter abnormalities in 15 out of 31 IGE patients, affecting regions including the temporal lobe, frontal lobe, limbic lobe, occipital lobe, brainstem, insular lobe, parietal lobe, thalamus and cerebellum. Intergroup DIR-SPM analysis comparing IGE patients to healthy controls showed a significant increase in gray matter density in the left temporal lobe ( x = -44, y = -56, z = 6, Z score = 4.58, PFWE = 0.041; x = -48, y = -40, z = -12, Z score = 4.54, PFWE = 0.047). Generalized spike wave discharges (GSWDs) were positively correlated with the number of voxels exhibiting significantly altered gray matter intensity in each individual with IGE (PFDR = 0.032). However, the multiple regression model did not identify any significant brain regions influencing the occurrences of GSWDs. In the IGE group, various regions exhibited alterations in gray matter density according to either individual or group DIR-SPM analysis. The frequency of GSWDs were correlated with the abnormal voxel count across the entire brain cortex of each individual with IGE.

CST3-related leukoencephalopathy is a recently recognized adult-onset neurodegenerative disorder caused by pathogenic CST3 variants with C-terminal truncations, frameshifts, or deletions. Owing to the limited number of reported cases, its clinical and radiological spectrum remains incompletely defined. Here, we report a Chinese family harboring a novel heterozygous nonsense variant of CST3 (c.327C > A; p.Cys109*), which represents the most 5’ pathogenic mutation identified to date. The proband, a 62-year-old woman, presented with recurrent encephalopathic episodes, progressive cognitive decline, tremor, urinary retention, and reduced serum cystatin C levels. Longitudinal MRI revealed extensive white matter lesions with persistent diffusion-weighted imaging (DWI) hyperintensities along the corticomedullary junction and the corpus callosum, which used to be viewed as a diagnostic marker of neuronal intranuclear inclusion disease. However, the possibility of neuronal intranuclear inclusion disease was excluded through comprehensive genetic and pathological evaluations. Notably, an asymptomatic young carrier already demonstrated white matter abnormalities with DWI hyperintensities, indicating that radiological changes can substantially precede clinical onset. Our findings expand the mutational and phenotypic spectrum of CST3-related leukoencephalopathy and highlight overlapping clinical and radiological features among adult-onset leukoencephalopathies presenting with corticomedullary junction DWI hyperintensities and episodic manifestations.

BACKGROUND:NOTCH2NLC-related neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by abnormal expansions of GGC repeats in the NOTCH2NLC gene. Traditional genetic testing relies on blood samples, which can be invasive. This study investigated the feasibility of using non-invasive saliva samples for detecting GGC repeat expansions in NIID patients. METHODS:Twenty-four NIID patients and twenty-one controls were enrolled. DNA was extracted from both blood and saliva samples using standard protocols. GGC repeat expansions were detected using triple-primed PCR (TP-PCR), followed by capillary electrophoresis to determine the repeat sizes. RESULTS:All NIID patients exhibited characteristic saw-tooth peaks indicative of GGC expansions in both saliva and blood tests, while control samples showed no such patterns. Saliva and blood genetic testing showed compa-rable GGC repeat expansions. Notably, one patient showed inter-tissue discrepancies, suggesting somatic mosaicism. CONCLUSIONS:Saliva DNA testing offers a reliable, minimally-invasive alternative to blood DNA testing for NIID diagnosis. While tissue-specific mosaicism may cause minor discrepancies, saliva's ease of collection and diagnostic accuracy support its utility in large-scale screening and early intervention strategies.

Objective While proline-rich transmembrane protein 2 (PRRT2) variants have been reported in association with self-limited infantile epilepsy (SeLIE), their relevance to adult epilepsy remains largely uncharacterized. Therefore, we investigated the prevalence of PRRT2 variants in an adult epilepsy cohort to broaden their phenotypic spectrum. Methods In a cohort of adult patients with epilepsy who underwent whole-exome sequencing (WES), individuals harboring PRRT2 variants were identified and selected for further analysis. Amino acid conservation among species, combined with functional verification of mutant proteins, was performed to assess the pathogenicity of novel PRRT2 variants. Furthermore, electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) were conducted in patients carrying PRRT2 variants. Results Two novel missense variants (c.643C > A/ p.P215T and c.932G > A/ p.R311Q) were demonstrated to impair protein expression, indicating a likely haploinsufficiency mechanism. Nine cases were identified carrying PRRT2 variants, including the c.649dupC hotspot variant and two missense variants. The age of seizure onset was predominantly during infancy or adolescence, with epilepsy persisting or relapsing into adulthood. Drug-resistant epilepsy was observed in two cases, whereas others were primarily controlled through sodium channel blockers. Unlike previously reported normal interictal EEG findings in PRRT2-related disorders, epileptiform discharges were recorded in the majority of patients. fMRI revealed reduced thalamocortical connectivity, indicating disrupted brain network integration. Conclusions This study expands the genotypic and phenotypic spectrum of PRRT2-related disorders, links its variants to epileptiform discharges, and reveals impaired network integration in PRRT2-associated epilepsy.

Human exceptional cognition stems from evolutionarily derived cortical adaptations that drive expansive neurogenesis. In this study, we employ the gyrencephalic ferret model to systematically characterize the molecular profiles and lineage dynamics of cortical radial glia (RGs). By applying scRNA-Seq to ferret and human cortices, we identify conserved regulatory programs underlying cortical neurogenesis and gliogenesis. We show that, similar to their human counterparts, ferret cortical outer radial glia (oRGs), exhibit enhanced ERK and PKA signaling. ERK and PKA act in a mutually reinforcing manner to boost oRG self-renewal and neurogenesis, while inhibiting gliogenesis and prolonging the neurogenic period. Furthermore, we identify regional specialization within cortical gliogenic RGs: YAP/TAZ activation drives ventricular zone truncated radial glia (tRGs) toward ependymal glial fate in medial cortex, whereas SHH signaling instructs tRGs within the ventrolateral-to-dorsal cortical axis to generate tripotential intermediate progenitor cells, which serve as a shared source of astrocytes, oligodendrocytes, and cortically-derived olfactory bulb interneurons. Our findings support a model in which cortical neurogenesis, gliogenesis, and evolutionary expansion are co-regulated through an integrated signaling network orchestrated by ERK, PKA, YAP/TAZ, and SHH. This network relies on a precisely balanced interplay of mutual inhibition among these pathways to ensure proper developmental outcomes.

BackgroundShared pathophysiological mechanisms exist between epilepsy and its associated comorbidities, with neuroinflammation playing a key role. 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) is a soluble epoxide hydrolase (sEH) inhibitor that exhibits potent, broad-spectrum anti-inflammatory effects by preventing the hydrolysis of epoxyeicosatrienoic acids (EETs). However, the potential anti-epileptic and comorbidity-alleviating effects of TPPU, along with the underlying molecular mechanisms, remain to be elucidated.MethodsElectroencephalogram (EEG) recordings and Racine score were used to monitor seizures. Behavioral tests were employed to assess seizure-associated cognitive and anxiety-like comorbidities in mice. Whole-cell patch-clamp recordings were used to evaluate synaptic function. RNA-sequencing was conducted to elucidate the molecular mechanisms underlying the neuroprotective effects of TPPU in the KA-induced chronic epileptic model.ResultsBehavioral assessments, EEG monitoring, and whole-cell patch-clamp recordings revealed that TPPU significantly mitigated seizure severity and anxiety/depressive-like behaviors, and enhanced cognitive function in kainic acid (KA)-induced chronic epileptic mice. TPPU exhibited neuroprotective properties by reducing neuronal apoptosis and neuroinflammation. Bulk RNA-sequencing analysis indicated that TPPU protected against neuroinflammation during epileptogenesis. Mechanistic investigations revealed that TPPU suppresses Akt/mTOR pathway activation.ConclusionsOur findings establish the Akt/mTOR axis as a critical pathway mediating the protective actions of TPPU against epilepsy and its comorbidities in murine models. This work not only advances our understanding of epilepsy pathophysiology but also identifies novel targets for the development of comprehensive therapeutic strategies.

Breathing rhythms bidirectionally modulate affective states, yet the underlying neural pathways remain elusive. Here, we identified an ascending neural circuit that integrates respiratory patterning with affective state in male mice. This circuit originates from glutamatergic neurons in the preBötzinger complex (preBötC), projecting to the paraventricular thalamic nucleus (PVT) and subsequently targeting the central amygdala (CeA). We reveal that photostimulation of the preBötC→PVT circuit significantly alleviates acute restraint stress-induced anxiety-like phenotypes and reduces respiratory frequency variability. Conversely, inhibition of this circuit exacerbates anxiety-like phenotypes and respiratory dysfunction. These effects are significantly abolished by inhibition or ablation of PVT neurons projecting to the CeA. Additionally, this anxiolytic effect is mediated by PVT projections that preferentially excite centrolateral amygdala neurons, thereby inhibiting centromedial amygdala output. Translating these findings, we show that volitional slow breathing reduces anxiety in healthy humans and suppresses anxiety-related beta/high-gamma oscillations in the amygdala of epilepsy patients. This work delineates a conserved respiratory-limbic circuit that mechanistically explains the anxiolytic effect of controlled breathing.