Zhi-Gan Formula improved insomnia and anxiety comorbidity in a mouse model via PACAP signaling in the medial prefrontal cortex.

A systematic review of ketamine and esketamine-induced long-term potentiation and synaptic scaling: Do the molecular and synaptic plasticity effects inform dosing intervals?

Abrogation of presynaptic facilitation at hippocampal mossy fiber synapses disrupts neural ensemble activity and spatial memory.

The MAP6-NTS axis in hippocampal CA1 regulates synaptic plasticity and memory.

Sulforaphane improved cognitive behavior in APP/PS1 mice via promoting structural and functional synaptic plasticity in the hippocampus.

Aggregation and deposition of TAR DNA-binding protein 43 (TDP-43) is a salient pathological signature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration-TDP (FTLD-TDP). TDP-43 proteostasis and aggregation are controlled by several posttranslational modifications, including ubiquitination. While multiple E3 ubiquitin ligases are known to facilitate TDP-43 clearance, little is known about the role of deubiquitinases (DUBs) in controlling TDP-43 proteostasis. Through an unbiased discovery screen of DUBs, here we identify and demonstrate using in vitro and in vivo models, as well as human brain tissue, that ubiquitin-specific peptidase-19 (USP19) acts as a TDP-43-directed DUB that removes K48- and K63-linked ubiquitin conjugates from TDP-43 and preferentially promotes cytoplasmic aggregation of TDP-43 C-terminal fragments (TDP-CTFs) through its catalytic activity. Specifically, the endoplasmic reticulum (ER)-anchored USP19 isoform (USP19-ER) exhibits superior activity in deubiquitinating TDP-CTFs, enhancing its phase separation and aggregation, compared to its cytosolic isoform (USP19-Cyto). Furthermore, as TDP-CTFs are generated at the ER, USP19 acts to couple the aggregation of TDP-CTFs to ER stress (ATF6, ATF4, IRE1, & CHOP). In humans, USP19 protein levels increase in FTLD-TDP brains, which extensively colocalize with cytoplasmic phospho-TDP-43 (pTDP-43) pathology. Importantly, we demonstrate in vivo that genetic reduction of usp19 mitigates pTDP-43 pathology, astrogliosis, and ER stress while reversing long-term potentiation (LTP) and motor deficits in a mouse model of TDP-43 pathogenesis (TAR4 mice). These findings establish a critical role of USP19 at the nexus of TDP-43 proteostasis and ER stress, implicating its pathogenic role in FTLD-TDP and ALS.

A ferroelectric/antiferroelectric (FE/AFE) bilayer HfxZr1-xO2(HZO) memcapacitor was fabricated to investigate asymmetric polarization and capacitance modulation governed by a built-in bias arising from the compositional gradient. This built-in bias facilitates polarization switching under negative bias while significantly suppressing forward switching under positive bias. Furthermore, it stabilizes the negatively poled state, leading to delayed relaxation and forming a wide capacitance memory window. Comparative AC and pulse analyses revealed the coexistence of a fast dipole component and a slow trapped-charge component. The AC read exhibited nonvolatile characteristics, while the pulse read showed volatile behavior with time-dependent charge decay. These differences explain the distinct retention and nondestructive read-out (NDRO) behaviors depending on the measurement scheme. The device demonstrated symmetric, highly linear long-term potentiation and depression, confirming its potential as a synaptic element for next-generation neuromorphic computing.

The high rate of comorbidity between metabolic diseases and neuropsychiatric disorders suggests a shared underlying pathogenic mechanism. However, the biological basis of this relationship remains unclear. This study aims to clarify the role of brain insulin resistance (BIR) in linking metabolic dysfunction to neuropsychiatric symptoms based on existing evidence. The analysis shows that BIR disrupts limbic system function through two primary molecular pathways: (1) impairment of the PI3K/Akt/mTOR pathway, which decreases the expression of synaptic plasticity-related proteins and causes deficits in long-term potentiation (LTP); (2) activation of the TLR4/MyD88 inflammatory axis, promoting pro-inflammatory cytokine release from glial cells. These changes result in characteristic neuropsychiatric phenotypes, including amygdala hyperactivity (emotional disorders), hippocampal atrophy (memory impairment), and decreased prefrontal cortex (PFC) function (executive dysfunction). This review highlights that interventions targeting BIR might simultaneously improve metabolic outcomes and neuropsychiatric symptoms, providing a theoretical foundation for trans-diagnostic treatment models. The findings support the view of BIR as a modifiable interface for metabolic- neuropsychiatric comorbidities and advocate for the development of a multidisciplinary collaborative framework to facilitate mechanism-based precision therapy.

Long-term regulation of inhibitory synaptic strength is crucial for maintaining excitation-inhibition (E/I) balance in cortical circuits. In this study, we identify neuroligin-2 (Nlgn2) as a critical mediator of inhibitory long-term potentiation (iLTP) in hippocampal CA1 pyramidal cells (PCs). Using neurolide-2, a synthetic dendrimeric peptide that selectively interferes with Nlgn2-neurexin binding, in combination with whole-cell recordings in mice hippocampal slices, we show that this interaction is required to maintain NMDA-induced iLTP. Disruption of Nlgn2-neurexin interactions blocked gephyrin clustering during iLTP and prevented Nlgn2 recruitment to GABAergic synapses, without effecting baseline inhibitory transmission. Immunostaining revealed that NMDA-induced enlargement of synaptic Nlgn2 clusters occurred selectively in the CA1 stratum oriens and was abolished by neurolide-2. Temporally controlled peptide application revealed a brief, 10-minute post-induction window during which Nlgn2-neurexin adhesion is required for iLTP consolidation, and later application had no effect. Optogenetic experiments further demonstrated that NMDA-induced iLTP at both somatostatin (SST) and parvalbumin (PV) inputs depends on Nlgn2. In a more physiological paradigm, high-frequency stimulation of excitatory inputs paired with postsynaptic CA1 PC depolarization triggered heterosynaptic iLTP selectively at SST→PC synapses, which was unaffected during induction but failed to consolidate when Nlgn2-neurexin interaction was blocked, whereas excitatory LTP and PV-mediated inhibition remained intact. These findings identify perisynaptic Nlgn2-neurexin adhesion as an activity-dependent mechanism supporting inhibitory plasticity depending on input identity and induction protocol. Disruption of this process may impair inhibitory circuit remodeling, contributing to E/I imbalance in neurodevelopmental and psychiatric disorders.Significance Statement The brain remains flexible and learns by adjusting the strength of excitatory and inhibitory synapses. While excitatory plasticity is well characterized, the rules guiding the induction and consolidation of inhibitory plasticity are less clear. We found that neuroligin-2, an adhesion protein that organizes inhibitory synapse formation, is also essential for inhibitory plasticity in the hippocampus, a brain region important for memory. Moreover, interference with neuroligin-2-dependent adhesion can erase already developed inhibitory plasticity within a short time window after induction, without affecting simultaneous plastic changes at excitatory synapses. These results highlight the consolidation phase of inhibitory plasticity and identify a mechanism that, if disturbed, may contribute to epilepsy, autism, and schizophrenia, which are linked to neuroligin-2 dysfunction.

GPR68, a proton-sensing GPCR, as a therapeutic target in depression: structural, signalling, and mechanistic perspectives.

Aging is accompanied by increasing inter-individual variability in cognitive and functional outcomes, reflecting differences in biological resilience and vulnerability. Chronic low-grade inflammation (inflammaging) is a central driver of this process, yet the contribution of individual inflammatory pathways to adaptive versus maladaptive brain aging remains incompletely understood. The NLRP3 inflammasome has been widely implicated in age-related neurodegeneration, but its physiological roles during adulthood and early aging are poorly defined. To delineate age-dependent functions of NLRP3 signaling, we combined behavioral, electrophysiological, and cellular analyses in adult (4-5months) and middle-aged (12-14months) wild-type and Nlrp3 knockout mice. Physical and cognitive decline were assessed using open field and fear conditioning paradigms. Hippocampal synaptic plasticity was evaluated by ex vivo recordings of long-term potentiation (LTP). Neural stem cells (NSCs) isolated from the hippocampus were used to quantify proliferation, neurogenic lineage markers, and glucose-related metabolic signaling. Acute pharmacological modulation of NLRP3 was examined using glibenclamide. Nlrp3 deletion markedly attenuated age-associated behavioral decline, resulting in preserved locomotor activity, learning, and memory and a substantially reduced prevalence of cognitive pre-frailty in middle-aged mice. In contrast, adult Nlrp3 knockout mice exhibited reduced hippocampal LTP, indicating that basal NLRP3 activity contributes to optimal synaptic function under physiological conditions. Aging was associated with a pronounced decline in LTP in wild-type mice, which was absent in Nlrp3-deficient mice and partially alleviated by glibenclamide. At the cellular level, Nlrp3 deficiency led to a persistent reduction in Nestin⁺ neural precursors and an exacerbation of age-related depletion of DCX⁺ neuroblasts, whereas proliferative capacity declined with aging independently of genotype. Metabolically, Nlrp3 knockout NSCs displayed constitutively reduced GLUT4 expression and complete prevention of the age-associated increase in GSK3β, a key regulator linking insulin signaling to neurodegenerative processes. Acute pharmacological inhibition selectively mitigated aging-related metabolic changes without restoring neurogenic deficits. These findings identify the NLRP3 inflammasome as a bidirectional regulator of brain aging. Basal NLRP3 activity supports the establishment of neurogenic, metabolic, and synaptic reserve in adulthood, whereas chronic activation during aging promotes metabolic dysregulation, synaptic vulnerability, and cognitive pre-frailty. The divergence between genetic ablation and acute pharmacological inhibition underscores the temporal specificity of NLRP3 signaling. Targeting inflammaging through selective, stage-specific modulation of NLRP3 may therefore represent a promising strategy to enhance cognitive resilience during aging.

Controllable bipolar doping in two-dimensional (2D) transition metal dichalcogenides (TMDs) remains a major challenge that limits their application in semiconductor information technologies. Realizing both controllable doping and nonvolatile carrier modulation of TMDs via a single fabrication process is crucial for implementing weight and activation regulation in neuromorphic computing. Here, we propose a facile strategy for WSe2 based on oxygen plasma-induced oxide layer formation and the generation of surface oxygen vacancies within the layer, in which precise regulation of the plasma flow rate enables tunable p-type and n-type doping. High flow rates induce the formation of WOx, while low flow rates generate oxygen vacancy-rich WOx, as confirmed by X-ray photoelectron spectroscopy. Kelvin probe force microscopy measurements further reveal surface potential shifts of -99 mV and +66 mV for WSe2 modified by stoichiometric WOx and vacancy-rich WOx, respectively, validating the bipolar doping mechanism. By exploiting the nonvolatile characteristics of oxygen vacancies, this doping strategy is integrated into a neuromorphic platform to fabricate high-performance transistor-type artificial synaptic devices with WOx serving as the surface-tunable oxide layer. Regulation of the ionization and migration of oxygen vacancies in the WOx layer via an external electric field endows the device with the capability to mimic key synaptic behaviors, including short-term plasticity/long-term plasticity, long-term potentiation, and long-term depression, and to exhibit 64 stable, programmable conductance states. When implemented in a reinforcement learning framework, the synaptic devices demonstrate adaptive decision-making capabilities. Importantly, a 6-bit in-memory computing model based on the proposed artificial synapse achieves an average dynamic-interaction reward of 5759.06, comparable to 5894.38 for a conventional 32-bit von Neumann system. This work provides an approach to the design of multifunctional hardware that achieves bipolar doping and neuromorphic computing in 2D semiconductors by introducing the same oxygen vacancy defects under different electrical modulation conditions.

Chronic pain (CP) is increasingly recognized not only as a sensory and emotional condition but also as a significant contributor to cognitive dysfunction. Growing evidence indicates that CP-induced cognitive dysfunction arises from a cascade of neurobiological processes, including persistent neuroinflammation, neurotransmitter dysregulation, and impaired synaptic plasticity. These mechanisms particularly affect the hippocampus and medial prefrontal cortex (mPFC)-regions essential for memory, attention, and executive function. Neuroimaging studies have documented structural atrophy and disrupted network connectivity in these brain areas in CP patients. At the molecular level, pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) impair glutamatergic and GABAergic signaling, disrupt long-term potentiation (LTP), and inhibit neurogenesis. Additionally, dysregulation of brain-derived neurotrophic factor (BDNF) signaling exacerbates synaptic vulnerability, contributing to cognitive decline. These mechanistic overlaps are particularly relevant in aging populations and in Alzheimer's disease (AD), where CP may act as a risk factor. This review integrates clinical and preclinical findings on CP-related cognitive dysfunction, outlines key molecular mechanisms, and explores emerging therapeutic strategies targeting inflammation, neurotransmitter systems, and synaptic repair. Understanding the interaction between chronic pain and cognition is critical for developing precision treatments that address both nociceptive and neurodegenerative pathways.

Cryopreserving the adult brain is challenging due to damage from ice formation, and traditional freezing methods fail to maintain neural architecture and function. Vitrification offers a promising alternative but has not been surveyed in the brain. Here, we demonstrate short-term recovery of the adult murine hippocampus after vitrification of brain slices and of the whole brain in situ. Key features of the hippocampus are preserved, including structural integrity, metabolic responsiveness, neuronal excitability, and synaptic transmission and plasticity. Notably, hippocampal long-term potentiation (LTP) was well preserved, indicating that the cellular machinery of learning and memory remains operational. These findings extend known biophysical limits for cerebral hypothermic shutdown by demonstrating recovery after complete cessation of molecular mobility in the vitreous state and thus contribute to achieving the objective of structural and functional preservation of neural tissue.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet effective preventive or therapeutic strategies remain limited. A hallmark of AD pathology is the accumulation of insoluble amyloid-β (Aβ) aggregates, which are targeted by recent antibody-based therapies. Conversely, soluble amyloid precursor protein-alpha (sAPPα), a non-amyloidogenic cleavage product of APP, possesses neuroprotective, neurotrophic, and synaptogenic properties, and the ability to enhance memory. This study evaluated the therapeutic efficacy of adeno-associated virus variant PHP.eB (AAV-PHP.eB) encoding human sAPPα in the APPswe/PS1dE9 transgenic mouse model of AD. Six-month-old female wild-type and transgenic mice received a single intravenous injection via the tail vein. Three months post-injection, brain tissue was harvested for electrophysiological and histological analyses. The treatment significantly increased cortical sAPPα levels and fully restored hippocampal long-term potentiation (LTP) in transgenic mice. Post-mortem analyses revealed a substantial reduction in amyloid plaque burden in both the hippocampus and cortex, with minimal plaque progression from the time of injection. However, no significant changes were observed in astrocytic (GFAP) or microglial (Iba-1) coverage, nor in soluble and insoluble Aβ1-40 or Aβ1-42 levels. These findings suggest that systemic AAV-PHP.eB-mediated sAPPα delivery can ameliorate synaptic dysfunction and aggregated amyloid pathology in AD, highlighting its potential as a therapeutic strategy.

Synaptic transmission between specific connection motifs undergoes plastic changes during the learning process; however, the exact mechanisms underlying synaptic plasticity are still under intense investigation. Long-term potentiation (LTP) of synaptic transmission is a widely used cellular model of synaptic plasticity occurring during learning. Here, we focused on studying LTP at excitatory synapses on layer (L) 2/3 vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) in the mouse somatosensory (barrel) cortex. LTP was induced by a pairing protocol of postsynaptic depolarization with extracellular stimulation in acute brain slices of young mice (P21-P28). The pairing protocol evoked LTP in L2/3 VIP-INs under control conditions; however, pharmacological blockade of GABAaR inhibition enhanced LTP. Next, we found that LTP in L2/3 VIP-INs is dependent on metabotropic glutamate receptor type 1 (mGluR-1) and L-type voltage-gated calcium channels (L-type VGCCs) but not on NMDARs or mGluR-5. Here, mGluR-1 acts through a G-protein-coupled signaling pathway and Src-family kinases, independently of transient receptor potential channels (TRPCs). Analyses of the paired-pulse ratio (PPR) and coefficient of variation (CV) indicate a presynaptic locus of LTP expression. Presynaptic expression of LTP in VIP-INs relies on retrograde signaling through endocannabinoids (eCBs) but not on brain-derived neurotrophic factor (BDNF). In conclusion, we dissected the mechanisms of LTP induction and expression at excitatory inputs to L2/3 VIP-INs in the mouse barrel cortex. LTP at excitatory synapses on VIP-INs might serve as a positive feedback for enhanced VIP-IN-mediated inhibition of SST-INs, leading to disinhibition of excitatory neurons from SST-IN inhibition during the learning process.

A full-function memristive associative memory neural network circuit based on multi-frequency SRDP rule.

Protective effects of sodium benzoate against toluene-induced reward enhancement, behavioral disturbances, and impaired synaptic plasticity in mice.

Memory reconsolidation is a re-stabilization phase in which memory is gradually changed from unstable to stable. This process is critical because unstable memories can be subject to modification or erasure if the reconsolidation phase is disrupted within a 6h time window. TrkB signaling pathway plays a key role in regulating neurogenesis, neuronal differentiation, maturation and survival. Numerous studies have reported that the TrkB signaling pathway participates in memory acquisition, consolidation and storage, although its role in memory reconsolidation is not fully understood. ANA-12, as a type of TrkB receptor inhibitor, can regulate various pain behaviors and attenuate propofol-induced apoptosis by blocking the TrkB signaling pathway. In this study, we investigated the effect of ANA-12 on memory reconsolidation in a novel object recognition (NOR) task. The results showed that ANA-12 injection immediately after the reactivation phase of the NOR task inhibited memory reconsolidation, whereas ANA-12 injection 6h after the reactivation phase had no effect on memory performance. ANA-12 injection 24h after the sample phase, with no subsequent reactivation phase, had no effect on memory performance. Transcriptome analysis demonstrated that ANA-12 administration significantly upregulated 347 genes and downregulated 79 genes in the hippocampus, compared to vehicle-treated animals. Those differentially expressed genes are involved in a wide range of functional pathways, including neuroinflammation, neurotransmitter synthesis, metabolism and transport, and long-term potentiation, which are all linked to memory impairment. These findings indicate that ANA-12-induced impaired memory reconsolidation is associated with changes in multiple signaling pathways.

Viral-mediated fluorescent labelling of activated hippocampal memory engrams to study epigenetic dynamics associated with gene expression.