Search Results (1,499)

Depressive disorders (DDs), especially treatment-resistant depression (TRD), pose a significant challenge worldwide, largely because their underlying biological mechanisms are complicated and treatments often fall short. There is growing evidence pointing to factors like disrupted neuroplasticity, neuroinflammation, irregularities in the hypothalamic–pituitary–adrenal (HPA) axis, and glutamatergic system imbalances as contributors to the onset and persistence of depressive symptoms. Exosomes (small extracellular vesicles involved in communication between cells) have recently gained attention for their potential role in connecting peripheral and central nervous system (CNS) changes. They carry proteins, lipids, and nucleic acids and are even capable of crossing the blood–brain barrier. Because of this, exosomes might provide a window into molecular changes in the brain and serve as accessible biomarkers of disease status and treatment response. Recent research points out that the contents of exosomes, especially microRNAs (miRNAs) and neurotrophic factors like brain-derived neurotrophic factor (BDNF), might play a part in disrupting synaptic plasticity and could be linked to resistance to antidepressants. At the same time, there is growing interest in using engineered exosomes as targeted drug carriers aimed at the CNS. That said, there are still quite a few hurdles to overcome. Methods vary widely between studies, protocols for isolating exosomes are not sufficiently standardized, safety data are limited, and we do not fully understand how drugs and exosomes interact or how they behave pharmacokinetically. This review brings together current findings regarding exosomes in DDs (with particular emphasis on TRD), highlights their promise for diagnosis and treatment, and sets out some of the main questions that need to be answered before clinical application becomes feasible. Full article

Hippocalcin (HPCA), a neuron-enriched calcium-binding protein, plays a critical role in brain function, but its role in neural precursor cells remains unclear. N-methyl-D-aspartate (NMDA) receptors are calcium-permeable glutamate receptors essential for neurodevelopment and synaptic plasticity, and their function has been implicated in neurological conditions. In this study, we investigated the role of HPCA in regulating NMDA receptor expression and function in mouse hippocampal neural precursor cells (mHNPCs). HPCA knockdown significantly reduced the expression of NMDA receptor-related genes, including Grin2C, Shank1, Serpine2, and selectively attenuated NMDA-induced calcium signaling. Transcriptomic analysis identified ELAV-like RNA-binding protein 3 (Elavl3), a neuron-enriched factor associated with neuronal activity, as a downstream candidate affected by HPCA knockdown. Consistently, Elavl3 suppression phenocopied HPCA deficiency, resulting in impaired NMDA receptor activity and reduced neuronal differentiation. Furthermore, hippocampal HPCA knockdown in vivo led to alterations in locomotor activity, contextual memory, and affective behaviors. Taken together, these findings demonstrate that HPCA supports NMDA receptor function and neuronal development, in part through Elavl3-associated pathways, and highlight HPCA as an important regulator of hippocampal function. Full article

Orthobiologic treatments such as platelet-rich plasma and stem cell therapies are increasingly used to support the healing of tendons, ligaments, and joints. This perspective proposes applying periodization—a structured, progressive model borrowed from athletic training—to rehabilitation following orthobiologic interventions in order to improve functional outcomes. The framework is organized into sequential phases that align with biological stages of healing. Early phases emphasize pain control, inflammation management, and safe, controlled mobility. Rehabilitation then progresses toward gradually increasing load bearing and strength, and toward more specific exercises to promote tissue regeneration while reducing the risk of re-injury. In later phases (mesocycles), the model highlights the importance of neuroplastic adaptations for sustained functional recovery, including neurogenesis, synaptic plasticity, and functional remodeling to safer RTP for athletes. A key advantage of this approach is its adaptability: progression can be individualized according to a patient’s recovery trajectory and response to loading. By aligning rehabilitation progression with intrinsic healing processes and integrating physiological and neuromuscular goals, the proposed model aims to maximize regenerative potential across both athletic and non-athletic populations. Overall, this neuroplastic periodized approach offers a practical, evidence-informed structure to guide clinicians in delivering patient-centered regenerative rehabilitation and may help standardize care after orthobiologic procedures. Full article

Background/Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which no disease-modifying therapy that halts or substantially slows disease progression is currently available. Although antibody therapies targeting amyloid β (Aβ) have recently received FDA approval, their high cost, limited efficacy, and potential adverse effects highlight the need for alternative solutions. Therefore, the development of low-molecular-weight compounds capable of reducing toxic Aβ aggregates is of considerable interest. In this study, we investigated the effects of 2,3,4-trihydroxybenzophenone (THB) on the inhibition and disassembly of Aβ_1–42 aggregates through in vitro and in vivo experiments. Methods: In vitro assays were performed to evaluate the effects of THB on Aβ_1–42 aggregation and fibril disassembly. Cell viability assays and hippocampal slice electrophysiology were conducted to assess neurotoxicity and synaptic function. In vivo effects were examined in Aβ_1–42 aggregate-injected mice and in 5 Familial AD mutations (5XFAD) mice using behavioral, histological, and electrophysiological analyses. Results: THB inhibited Aβ_1–42 aggregation in a concentration-dependent manner and promoted the disassembly of preformed fibrils. THB attenuated Aβ_1–42-induced Neuro2a cell death and restored Aβ_1–42 aggregate-associated long-term potentiation (LTP) deficits in hippocampal slices. In Aβ_1–42 aggregate-injected and 5XFAD mice, THB reduced amyloid pathology and neuroinflammatory markers and improved synaptic function and memory performance. Conclusions: These findings suggest that THB modulates pathogenic Aβ_1–42 assemblies and provides a structural basis for the development of small-molecule modulators of Aβ_1–42 aggregation with potential preventive or disease-modifying applications in AD. Full article

Background/Objectives: Blast-induced hearing loss (BIHL) is a major concern, particularly for military personnel, and is linked to impaired auditory neuron survival and synaptic plasticity. This study investigates the potential of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) to reduce the severity of BIHL and promote recovery in a mouse model. Methods: Eight-week-old male C57BL/6J mice were used. A custom-built, compressed air-driven system utilizing a modified paintball apparatus was employed to deliver controlled unilateral double blasts (~22 psi exposure pressure) to the left ear. The blasts were administered 30 min apart. Immediately following the second blast, mice received either 7,8-DHF (10 mg/kg) or vehicle (10% DMSO) via intraperitoneal injection. Auditory brainstem responses (ABRs) were measured in both ears at baseline (pre-blast) and at several post-exposure time points. Results: The consecutive blast exposure induced a significant elevation in ABR thresholds, indicative of hearing loss, in both the ipsilateral (exposed) and contralateral (unexposed) ears of vehicle-treated mice. Notably, mice treated with 7,8-DHF demonstrated a marked improvement in hearing recovery compared to the vehicle group. Significant reductions in ABR thresholds were observed in the ipsilateral ear at 4 weeks post-blast (p < 0.0001) and in the contralateral ear as early as 1-week post-blast (p = 0.0236). However, the recovery was partial, with ABR thresholds plateauing after 4 weeks. Conclusions: A controlled blast model demonstrates that systemic administration of the TrkB agonist 7,8-DHF exerts a protective effect, partially restoring auditory function after blast injury. This supports the therapeutic potential of targeting the BDNF-TrkB signaling pathway for managing BIHL. Full article

Locus coeruleus (LC) noradrenergic neurons project their axons to the cerebellar cortex and modulate cerebellar circuit function via distinct adrenergic receptor (AR) subtypes. The present study investigated the mechanism by which optogenetic activation of LC noradrenergic neurons modulates facial stimulation-evoked long-term synaptic plasticity at cerebellar mossy fiber-granule cell (MF-GrC) synapses in urethane-anesthetized DBH-Cre mice. Blockade of GABA_A receptors, 20 Hz facial stimulation induced MF-GrC long-term potentiation (LTP) in the control group, and this LTP was impaired by optogenetic activation of LC noradrenergic neurons via α2-ARs. Meanwhile, facial stimulation induced LTP of glutamate sensor fluorescence in the granular layer, which was abolished by chemogenetic activation of LC noradrenergic neurons. Following NMDA receptor blockade, optogenetic activation of LC noradrenergic neurons triggered facial stimulation-induced MF-GrC long-term depression (LTD) via α2A-ARs. Optogenetically activated LC noradrenergic neuron-induced MF-GrC LTD was abolished by protein kinase A (PKA) inhibition but not by protein kinase C inhibition. Immunofluorescence results revealed abundant α2A-AR expression in the granular layer, with particularly high levels in glomeruli, and no colocalization with the glutamate sensor. These results indicate that optogenetic activation of LC noradrenergic neurons impairs facial stimulation-induced MF-GrC LTP by triggering presynaptic LTD via the α2A-AR/PKA signaling cascade. Full article

Ischemic stroke is a leading cause of disability worldwide, marked by profound disruption of the neurovascular unit (NVU), a dynamic grouping of neurons, astrocytes, cerebral endothelial cells (CECs), microglia, pericytes, and oligodendrocytes. While acute stroke interventions such as tissue plasminogen activator and endovascular thrombectomy address reperfusion, they fail to engage the prolonged and cell-specific processes critical for recovery. Extracellular vesicles (EVs), membrane-bound carriers of proteins, lipids, and nucleic acids, have emerged as key modulators of intercellular communication within the NVU. This review synthesizes current evidence on NVU-derived EVs as both regulators and effectors of post-stroke pathology and repair. We highlight the phase-specific roles of EVs in modulating blood–brain barrier (BBB) integrity, thrombosis, angiogenesis, neurogenesis, oligodendrogenesis, synaptic plasticity, and neuroinflammation. This review places special emphasis on how EV cargo reflects the state of their parent cells and how EV-mediated crosstalk orchestrates coordinated neurorestorative responses. We further discuss the dual nature of EVs, their therapeutic potential for stroke, and the methodological challenges impeding clinical translation, including isolation standardization, cell-specific targeting, and regulatory barriers. Thus, adherence to minimal information for studies of extracellular vesicles (MISEV) guidelines is essential to ensure rigor, reproducibility, and transparency. When combined with temporal and cellular specificity, NVU-derived EVs may represent a biomimetic platform for promoting durable recovery in stroke patients. Full article

Background: Prenatal cannabinoid exposure (PCE) causes neurodevelopmental impairments affecting learning and memory; however, the receptor-level interactions underlying these cognitive deficits remain poorly understood. This study investigated whether a moderate dose of prenatal Δ⁹-tetrahydrocannabinol (THC) exposure alters the biophysical properties of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are critical mediators of excitatory neurotransmission and synaptic plasticity. Methods: Pregnant Sprague-Dawley rats received a moderate dose (5 mg/kg) of THC or vehicle control via oral gavage throughout gestation and early postnatal development. Single-channel electrophysiological activity of the AMPA receptors (AMPARs) was recorded using patch-clamp techniques on synaptosomal AMPARs reconstituted into artificial lipid bilayers from adolescent offspring. Western blot analysis of GluA1- and GluA2-containing AMPAR subunits and the postsynaptic scaffold protein postsynaptic density 95 (PSD95) was conducted to assess protein levels. Results: Prenatal THC exposure decreased AMPAR open-channel probability, reduced mean open time, increased mean closed time, and altered burst channel activity significantly, without altering GluA1, GluA2, or PSD95 protein levels. Furthermore, the interactive channel-gating activity observed in control synaptosomes was absent in synaptosomes derived from THC-exposed offspring. Conclusions: Prenatal cannabinoid exposure induces early alterations in glutamatergic synaptic function primarily mediated by changes in AMPAR channel kinetics rather than receptor abundance. By identifying AMPAR single-channel dysfunction as a sensitive marker of PCE-induced synaptic disruption, this work provides a mechanistic framework linking prenatal THC exposure to long-term alterations in learning and memory. Full article

Background/Objectives: Alzheimer’s disease (AD) involves amyloid-β (Aβ) deposition, oxidative stress, and neuroinflammation, leading to cognitive decline. Nobiletin, a citrus-derived polymethoxylated flavonoid, exerts antioxidant and anti-inflammatory effects. This study explored its neuroprotective mechanisms in the 5XFAD mouse model. Methods: Male 5XFAD and C57BL/6J mice received oral nobiletin (20 or 40 mg/kg/d) for 4 weeks. Cognitive function was assessed by the Y-maze test. Amyloid-β burden was quantified by Congo red staining and ELISA. Serum cytokine levels and antioxidant enzyme activities were measured by ELISA. Western blotting and RT-PCR were used to assess proteins and genes related to amyloidogenesis, inflammation (TLR4/MyD88/NF-κB), mitochondrial biogenesis (AMPK/SIRT1/PGC-1α), and synaptic plasticity (PI3K/Akt–CREB–BDNF). Results: Nobiletin improved working memory, reduced amyloid-β40/42 deposition, and downregulated APP, BACE1, and PS1 expression, while enhancing ADAM10 expression. It lowered serum IL-6, IL-1β, and TNF-α, increased SOD, CAT, and GPx activities, and suppressed TLR4/MyD88/NF-κB signaling. Furthermore, it activated AMPK/SIRT1/PGC-1α and NRF2 pathways, enhancing antioxidant defenses, and promoted PI3K/Akt–CREB–BDNF signaling, increasing PSD95 and synaptophysin. Conclusions: Nobiletin exerts strong neuroprotective and antioxidant effects by targeting multiple signaling cascades, mitigating amyloid pathology and neuroinflammation, and improving synaptic plasticity. It represents a promising therapeutic agent against AD. Full article

Astrocytes critically regulate states of consciousness, yet their molecular profiles across wake, sleep, and general anesthesia remain unclear. This study conducted proteomic and phosphoproteomic analyses of rat cortical astrocytes across these states using sevoflurane. Data quality was validated using principal component analysis (PCA) and Pearson correlation coefficient (PCC). Proteomics showed state-specific signatures: sleep and anesthesia shared similar changes (downregulated structural proteins, upregulated membrane transport complexes) but diverged in molecular expression. Anesthesia specifically suggested potential activation of cellular differentiation/structural plasticity-related pathways but implied potential disruption of metabolism and molecular clearance processes compared to sleep. Phosphoproteomics revealed the unique phosphorylation changes during general anesthesia compared to wake and normal sleep: downregulated phosphorylation of nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) at Ser188, suggesting the potential suppression of nuclear transcription and/or cell cycle activity, which may act as a potential molecular signature associated with the anesthetic state. Clustering analysis showed that sleep was associated with upregulated mRNA processing, while anesthesia indicated potential enhancement of synaptic signaling and suggested possible suppression of development-related programs. In summary, astrocytes undergo extensive molecular reprogramming during transitions of consciousness; while they share common features in morphological remodeling, sleep and anesthesia differ fundamentally in astrocytic molecular outcomes, offering new insights into astrocytic roles in unconsciousness. Full article

In the post-Moore’s Law era, conventional Von Neumann architectures face critical limitations, such as the “memory wall” and excessive power consumption, particularly when processing unstructured data. Neuromorphic computing, inspired by the human brain, offers a promising solution through parallel processing and adaptive learning. Among the candidates for artificial synapses, memristors based on two-dimensional MXenes (specifically Ti₃C₂T_x) have attracted significant attention due to their unique layered structure, high metallic conductivity, and tunable physicochemical properties. This review provides a comprehensive analysis of MXene-based memristors, from material synthesis to system-level applications. We examine how different synthesis strategies, including etching methods, directly influence device performance and elucidate the underlying resistive switching mechanisms driven by ion migration, valence change, and interfacial processes. Furthermore, the review demonstrates the efficacy of MXenes in emulating biological synaptic functions—such as spike-timing-dependent plasticity (STDP) and long-term potentiation/depression (LTP/LTD)—and their application in tasks like handwritten digit recognition. Finally, we highlight emerging frontiers in flexible electronics and in-sensor computing, offering insights into the future trajectory of integrated sensing, memory, and computation. Full article

Background/Objectives: Stewartia pseudocamellia Maxim. (S. pseudocamellia) has been reported to possess antioxidant and anti-inflammatory properties and contains various bioactive flavonoids and phenolic compounds. These components may contribute to neuroprotective effects relevant to depression and cognitive dysfunction. This study was conducted to evaluate the effects of 20% ethanolic extract from S. pseudocamellia leaves (ESP) on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and cognitive dysfunction in C57BL/6 mice. Methods: C57BL/6 mice were divided into six groups: normal control (NC), normal sample (NS; ESP 100 mg/kg), CUMS, L-theanine (Thea; 4 mg/kg), ESP 50 mg/kg, and ESP 100 mg/kg groups. Phytochemical profiling of ESP was performed using ultra-performance liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Depressive-like behaviors and cognitive function were assessed, along with stress-related hormonal regulation and associated cellular signaling pathways. Results: Phytochemical profiling of ESP identified procyanidin B2, epicatechin, rutin, catechin gallate, kaempferol 3-O-glucoside, and quercitrin as major constituents. ESP significantly alleviated CUMS-induced depressive-like behaviors and improved spatial learning and memory. These effects were associated with modulation of stress-related hormones in serum and hypothalamic–pituitary–adrenal (HPA) axis–related proteins in the brain. ESP also enhanced antioxidant defense by activating the Nrf2 signaling pathway and improving mitochondrial function. Furthermore, ESP attenuated neuroinflammation and apoptosis by regulating the TLR4/NF-κB and JNK pathways, and promoted neuroplasticity by modulating cholinergic activity, with enhanced BDNF/TrkB signaling in the cerebral cortex and hippocampus. Conclusions: Collectively, these findings suggest that ESP exerts protective effects against CUMS-induced depressive-like behaviors and cognitive deficits in a preclinical model. Full article

This paper presents a compact floating memtranstor (MT) emulator, a memory element characterized by a direct φ–q relationship, realized without analog multipliers or complex circuitry. The proposed design employs only two active blocks—a voltage differential transconductance amplifier (VDTA) and a voltage differential current conveyor (VDCC)—along with three grounded capacitors and a single grounded electronically tunable resistor. The emulator accurately reproduces the fundamental φ–q dynamics, exhibiting origin-crossing pinched hysteresis loops under sinusoidal excitation, and operates at a low supply voltage of ±0.9 V. Electronic tunability is achieved via bias-controlled transconductance modulation, enabling flexible adaptation across excitation frequencies and operating conditions. Validation is performed through analytical modeling, Monte Carlo simulations, temperature sensitivity analysis, and full LTspice post-layout simulations using a 180 nm CMOS process. The full-custom layout occupies 2529.49 μm², with robust performance confirmed under parasitic and process variations. Adaptive learning simulations demonstrate the emulator’s artificial synaptic plasticity, highlighting its suitability for neuromorphic computing, chaos-based circuits, and nonlinear dynamical systems. The compact, low-power, and multiplier-free architecture establishes the proposed MT emulator as a practical platform for emerging analog memory-centric applications. To validate the feasibility of the proposed solution, experimental tests are performed using commercially available components. Full article

Electrophysiology, mechanobiology, and the study of soft matter within cells demonstrate increasing amounts of evidence that neuronal signaling arises from interactions between membrane potential, force, and phase. Herein, we have attempted to collect and organize the evidence for each of these areas of study into an approximate structure called the electromechanical connectome: a three-way state–space (membrane potentials, nanoscale mechanical forces, and cytoplasmic rheology, including phase-separated liquid–liquid droplets) where membrane potentials, nanoscale mechanical forces, and cytoplasmic rheology, and phase-separated liquid–liquid droplets are likely to influence one another, influencing synaptic processing, plasticity and network stability. We will also attempt to illustrate the following: how changes in electrostatic fields can be used to alter the arrangement of lipids, hydration, and dielectric microdomains, and the contact geometry between organelles and activity dependent transcription; how mechanical dynamics associated with spines, axons, and the active zone of synapses may be used to modify the energy landscape of channels, the docking and priming of vesicles, and the transport of cytoskeletons; and how viscosity corridors, along with phase-separated micro-reactors, can be used to regulate the kinetics of signaling, molecular trafficking and metabolic processes in local environments. With these connections in mind, we will propose a multiphysical attractor model in which cognition is the result of navigating through metastable manifolds, while neurodegenerative disease may be a result of the progressive loss of electromechanical coherence, phase boundary control and energetic flexibility. Finally, we will present testable hypotheses and use AI-enabled digital twin methods to potentially quantify the early deformation of manifolds and provide precision biomarkers and therapeutic options. Full article

Background/Objectives: Unpredictable chronic mild stress exposure is a primary driver of cognitive decline, largely mediated by hypothalamic–pituitary–adrenal (HPA) axis dysregulation and subsequent oxidative neurotoxicity. In traditional Thai medicine, the AYW-KK-04 formulation—a complex polyherbal remedy—has long been utilized as a “Ya Aayu-Wattana” to restore vitality and elemental balance, yet its neurobiological mechanisms remain poorly understood. This study aimed to evaluate the adaptogenic and neuroprotective potential of AYW-KK-04 against cognitive impairment. Methods: Unpredictable Chronic Mild Stress (UCMS)-induced cognitive impairment in a ICR mouse model. Total phenolic and flavonoid contents and antioxidant capacity (ABTS assay) of AYW-KK-04 were determined. Behavioral assessments using Y-maze test, novel object recognition test (NORT), and Morris Water Maze (MWM) test. BDNF, CREB, Nrf and Keap1 mRNA gene expression, SOD and CAT enzymatic activity and lipid peroxidation assay were investigated to clarify the mechanisms of action. Moreover, HPLC chromatography was studied to quantify the active compounds of the AYW-KK-04 formulation. Results: It demonstrated that oral administration of AYW-KK-04 significantly reversed UCMS-induced memory deficits. At the molecular level, AYW-KK-04 effectively upregulated BDNF and CREB mRNA expression in the frontal cortex and hippocampus, suggesting a restoration of synaptic plasticity. Simultaneously, the formulation activated the Nrf2/Keap1 signaling pathway, leading to enhanced SOD and CAT enzymatic activities and a marked reduction in MDA-mediated lipid peroxidation. HPLC analysis confirmed the presence and consistency of key bioactive constituents. Conclusions: These findings suggest that the adaptogenic properties of AYW-KK-04 arise from its dual capacity to reinforce neurotrophic support and bolster the endogenous antioxidant shield, providing a mechanistic support for the traditional use of AYW-KK-04 as an adaptogenic formulation and highlighting its potential as a multi-target intervention for stress-related cognitive dysfunction. Full article