Search Results (183)

B-raf (rapidly accelerated fibrosarcoma) is a crucial player within the ERK/MAPK signaling pathway. In the CNS, B-raf has been implicated in neuronal differentiation, long-term memory, and major depression. Mice with forebrain neuron-specific B-raf knockout show behavioral deficits in spatial learning tasks and impaired hippocampal long-term potentiation (LTP). To elucidate the mechanism(s) underlying diminished synaptic plasticity in B-raf-deficient mice, we performed whole-cell recordings from CA1 pyramidal cells in hippocampal slices of control and B-raf mutant mice. We found that the NMDA/AMPA ratio of excitatory postsynaptic currents (EPSCs) at the Schaffer collateral—CA1 pyramidal cell synapses was significantly reduced in B-raf mutants, which would at least partially account for their impaired LTP. Interestingly, the reduced NMDA component of field postsynaptic potentials in mutant preparations was partially reinstated by blocking the apamin-sensitive small-conductance Ca²⁺-activated K⁺ (SK) channels, which have also been reported to modulate hippocampal LTP and learning tasks. To determine the impact of B-raf-dependent signaling on SK current, we isolated the apamin-sensitive tail current after a strong depolarizing event and found indeed a significantly bigger SK current in B-raf-deficient cells compared to controls, which is consistent with the reduced action potential firing and the stronger facilitating effect of apamin on CA1 somatic excitability in B-raf-mutant hippocampus. Our data suggest that B-raf signaling readjusts the delicate balance between NMDA receptors and SK channels to promote synaptic plasticity and facilitate hippocampal learning and memory. Full article

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe X-linked neurodevelopmental condition characterized by early-onset, intractable epilepsy, motor and cognitive impairment, and autistic-like features. Although constitutive Cdkl5 knockout (KO) models have established the importance of CDKL5 during early brain development, CDKL5’s role in the mature brain remains poorly defined. Here, we employed an inducible, conditional KO model in which Cdkl5 is selectively deleted from forebrain glutamatergic neurons in adult mice to investigate the postdevelopmental functions of CDKL5. Using a total of 48 adult male mice, including Cdkl5^flox/Y(Cre⁺) (n = 30) and Cdkl5^flox/Y(Cre⁻) littermate controls (n = 18), we found that tamoxifen-induced Cdkl5 deletion led to prominent behavioral impairments, including deficits in motor coordination, reduced sociability, and impaired hippocampus-dependent spatial memory, while behavioral features such as hyperactivity and stereotypic jumping, typically present in germline KOs, were absent. Sensory functions, including olfaction and pain perception, were also preserved. At the cellular level, the loss of Cdkl5 resulted in a marked reduction in excitatory synapse density in the cortex and hippocampus, accompanied by increased numbers of immature dendritic spines and decreased mature spines. Neuronal loss in the hippocampal CA1 region and selective microglial activation in the cortex were also observed. These alterations closely resemble those seen in constitutive KO models, underscoring the ongoing requirement for CDKL5 expression in excitatory neurons for maintaining synaptic integrity and neuronal homeostasis in the adult brain. This study underscores the importance of temporally controlled models for investigating the mechanisms underlying CDD pathophysiology in the adult brain. Full article

Synaptic plasticity is the key mechanism underlying learning and memory. Neurexins are pre-synaptic molecules that play a pivotal role in synaptic plasticity, interacting with many different post-synaptic molecules in the formation of neural circuits. Neurexins are alternatively spliced at different splice sites, yielding thousands of isoforms with different properties of interaction with post-synaptic molecules for a quick adaptation to internal and external inputs. The endocannabinoid system also plays a central role in synaptic plasticity, regulating key retrograde signaling at both excitatory and inhibitory synapses. This study aims at elucidating the crosstalk between alternative splicing of neurexin and the endocannabinoid system in the hippocampus. By employing an ex vivo hippocampal system, we found that pharmacological activation of cannabinoid receptor 1 (CB1) with the specific agonist ACEA led to reduced neurotransmission, associated with increased expression of the Nrxn1–3 spliced isoforms excluding the exon at splice site 4 (SS4−). In contrast, treatment with the CB1 antagonist AM251 increased glutamatergic activity and promoted the expression of the Nrxn variants including the exon (SS4+) Knockout of the involved splicing factor SLM2 determined the suppression of the exon splicing at SS4 and the expression only of the SS4+ variants of Nrxns1–3 transcripts. Interestingly, in SLM2 ko hippocampus, modulation of neurotransmission by AM251 or ACEA was abolished. These findings suggest a direct crosstalk between CB1-dependent signaling, neurotransmission and expression of specific Nrxns splice variants in the hippocampus. We propose that the fine-tuned regulation of Nrxn1–3 genes alternative splicing may play an important role in the feedback control of neurotransmission by the endocannabinoid system. Full article

We report the fabrication and characterization of Al-doped ZnO (AZO) optoelectronic synaptic devices based on sol–gel-derived thin films with varying Al concentrations (0~4.0 wt%). Structural and optical analyses reveal that moderate Al doping modulates the crystal orientation, optical bandgap, and defect levels of ZnO films. Notably, 2.0 wt% Al doping yields the widest bandgap (3.31 eV), stable PL emission, and uniform deep-level absorption without inducing significant lattice disorder. Synaptic performance, including learning–forgetting dynamics and persistent photoconductivity (PPC), is strongly dependent on Al concentration. The 2.0 wt% AZO device exhibits the lowest forgetting rate and longest memory retention due to optimized trap formation, particularly Al–oxygen vacancy complexes that enhance carrier lifetime. Visual memory simulations using a 3 × 3 pixel array under patterned UV illumination further confirm superior long-term memory (LTM) behavior at 2.0 wt%, with stronger excitatory postsynaptic current (EPSC) retention during repeated stimulation. These results demonstrate that precise doping control via the sol–gel method enables defect engineering in oxide-based neuromorphic devices. Our findings provide an effective strategy for designing low-cost, scalable optoelectronic synapses with tunable memory characteristics suitable for future in-sensor computing and neuromorphic vision systems. Full article

Artificial photoelectric synapses exhibit great potential for overcoming the Von Neumann bottleneck in computational systems. All-inorganic halide perovskites hold considerable promise in photoelectric synapses due to their superior photon-harvesting efficiency. In this study, a novel wavy-structured CsPbBr₃/ZnO hybrid film was realized by depositing zinc oxide (ZnO) onto island-like CsPbBr₃ film via atomic layer deposition (ALD) at 70 °C. Due to the capability of ALD to grow high-quality films over small surface areas, dense and thin ZnO film filled the gaps between the island-shaped CsPbBr₃ grains, thereby enabling reduced light-absorption losses and efficient charge transport between the CsPbBr₃ light absorber and the ZnO electron-transport layer. This ZnO/island-like CsPbBr₃ hybrid synaptic transistor could operate at a drain-source voltage of 1.0 V and a gate-source voltage of 0 V triggered by green light (500 nm) pulses with low light intensities of 0.035 mW/cm². The device exhibited a quiescent current of ~0.5 nA. Notably, after patterning, it achieved a significantly reduced off-state current of 10⁻¹¹ A and decreased the quiescent current to 0.02 nA. In addition, this transistor was able to mimic fundamental synaptic behaviors, including excitatory postsynaptic currents (EPSCs), paired-pulse facilitation (PPF), short-term to long-term plasticity (STP to LTP) transitions, and learning-experience behaviors. This straightforward strategy demonstrates the possibility of utilizing neuromorphic synaptic device applications under low voltage and weak light conditions. Full article

Adolescent binge drinking has lasting behavioral consequences by disrupting the endocannabinoid system (ECS) and depleting brain omega-3. The natural accumulation of omega-3 fatty acids in cell membranes is crucial for maintaining the membrane structure, supporting interactions with the ECS, and restoring synaptic plasticity and cognition impaired by prenatal ethanol (EtOH) exposure. However, it remains unclear whether omega-3 supplementation can mitigate the long-term effects on the ECS, endocannabinoid-dependent synaptic plasticity, and cognition following adolescent binge drinking. Here, we demonstrated that omega-3 supplementation during EtOH withdrawal increases CB1 receptors in hippocampal presynaptic terminals of male mice, along with the recovery of receptor-stimulated [³⁵S]GTPγS binding to Gαi/o proteins. These changes are associated with long-term potentiation (LTP) at excitatory medial perforant path (MPP) synapses in the dentate gyrus (DG), which depends on anandamide (AEA), transient receptor potential vanilloid 1 (TRPV1), and N-methyl-D-aspartate (NMDA) receptors. Finally, omega-3 intake following binge drinking reduced the time and number of errors required to locate the escape box in the Barnes maze test. Collectively, these findings suggest that omega-3 supplementation restores Barnes maze performance to levels comparable to those of control mice after adolescent binge drinking. This recovery is likely mediated by modulation of the hippocampal ECS, enhancing endocannabinoid-dependent excitatory synaptic plasticity. Full article

Background: Inner hair cell (IHC) ribbon synapses are the initial synapses in the auditory pathway, comprising presynaptic ribbons and postsynaptic glutamate receptors on the peripheral afferent fibers. The excitatory neurotransmitter glutamate primarily signals through AMPA-type heterotetrameric receptors (AMPARs), composed of GluR1, GluR2, GluR3, and GluR4 subunits. Research shows that corticosterone affects AMPA receptor subunits in the central nervous system. The present study investigates the effects of corticosterone on AMPA receptor subunits in the murine cochlea. Methods: Cochlear explants were isolated from male and female C57BL/6 pups (postnatal days 4–5), treated for 20 min with 100 nM corticosterone, and cultured for an additional 24 h. The concentration of AMPAR protein subunits was quantified using an ELISA assay, while gene expression was analyzed using RT-PCR. The synaptic localization patterns of GluR2 and Ribeye were examined using immunofluorescence and confocal microscopy. Results: Male C57BL/6 mice have a significantly greater basal concentration of the GluR2 subunit than females and more GluR2 puncta per IHC than females. Corticosterone increases the size of Ribeye in males and increases twofold GluR2/Ribeye colocalization in the apical region of females. Conclusions: Exposure of membranous cochleae to corticosterone induces changes consistent with neuroplasticity in the auditory periphery. The observed effect is sex-dependent. Full article

Major depressive disorder (MDD) is a common psychiatric disorder characterized by significant mood disturbances and cognitive impairments. Chronic stress, particularly social defeat stress, plays a crucial role in the etiology of depression, with oxidative stress being a pivotal factor in its pathophysiology. Consequently, identifying effective strategies to mitigate oxidative stress and prevent the progression of depression is of paramount importance. Agomelatine, an atypical antidepressant with melatonergic and serotonergic properties, has shown promise in treating MDD due to its unique mechanisms of action. In this study, we aimed to investigate whether agomelatine could ameliorate behavioral deficits in a chronic social defeat stress (CSDS) mouse model. CSDS mice were administered agomelatine (50 mg/kg, intraperitoneally) and exhibited significant reductions in both anxiety-like and depressive-like behaviors in behavioral tests. Further analysis revealed that agomelatine treatment effectively reduced oxidative damage in the hippocampus of CSDS mice. Additionally, agomelatine attenuated mitochondrial dysfunction and restored synaptic plasticity, as evidenced by an increased density of excitatory synapses and enhanced neuronal activity. These findings suggest that agomelatine may exert therapeutic effects by reducing oxidative stress, preserving mitochondrial function, and enhancing synaptic plasticity, providing new insights into its potential as a treatment for chronic social defeat stress-induced depression. Full article

Background and Objectives: Docosahexaenoic acid (DHA) has been shown to modulate various voltage-gated ion channels and both excitatory and inhibitory synapses. Nonetheless, its exact effect on nociceptive signaling in the trigeminal system has yet to be elucidated. The purpose of the current investigation was to assess if acute DHA given intravenously to rats diminished the excitability of wide dynamic range spinal trigeminal nucleus caudalis (SpVc) neurons in response to mechanical stimulation in vivo. Methods: Single-unit extracellular activity was recorded from SpVc neurons in response to mechanical stimulation of the whisker pad in anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. Results: The mean firing frequency of SpVc wide dynamic range neurons in response to both non-noxious and noxious mechanical stimuli was significantly dose-dependently inhibited by DHA, and the effect was seen within 5 min. After approximately 20 min, the inhibiting effects dissipated. Conclusions: These results suggest that, in the absence of inflammatory or neuropathic pain, the acute intravenous administration of DHA reduces the activity of trigeminal sensory neurons, including those responsible for pain, indicating that DHA could be utilized as an adjunct and alternative therapeutic agent for managing trigeminal nociceptive pain, including hyperalgesia. Full article

Two-terminal optoelectronic synaptic devices based on ZnO nanoparticles (NPs) were fabricated to investigate the effects of thermal annealing control (200 °C–500 °C) in nitrogen and oxygen atmospheres on surface morphology, optical response, and synaptic functionality. Atomic force microscopy (AFM) analysis revealed improved grain growth and reduced surface roughness. At the same time, UV–visible spectroscopy and photoluminescence confirmed a blue shift in the absorption edge and enhanced near-band-edge emission, particularly in nitrogen-annealed devices due to increased oxygen vacancies. X-ray photoelectron spectroscopy (XPS) analysis of the O 1s spectra confirmed that oxygen vacancies were more pronounced in nitrogen-annealed devices than in oxygen-annealed ones at 500 °C. Optical resistive switching was observed, where 365 nm ultraviolet (UV) irradiation induced a transition from a high-resistance state (HRS) to a low-resistance state (LRS), attributed to electron–hole pair generation and oxygen desorption. The electrical reset process, achieved by applying −1.0 V to −5.0 V, restored the initial HRS, demonstrating stable switching behavior. Nitrogen-annealed devices with higher oxygen vacancies exhibited superior synaptic performance, including higher excitatory postsynaptic currents, stronger paired-pulse facilitation, and extended persistent photoconductivity (PPC) duration, enabling long-term memory retention. By systematically varying UV exposure time, intensity, pulse number, and frequency, ZnO NPs-based devices demonstrated the transition from short-term to long-term memory, mimicking biological synaptic behavior. Learning and forgetting simulations showed faster learning and slower decay in nitrogen-annealed devices, emphasizing their potential for next-generation neuromorphic computing and energy-efficient artificial synapses. Full article

Glioblastoma (GB) treatment, despite consisting of surgical resection paired with radiation, temozolomide chemotherapy and tumor-treating fields, yields a median survival of 15–20 months. One of the more recently appreciated hallmarks of GB aggressiveness is the co-opting of neurotransmitter signaling mechanisms that normally sustain excitatory synaptic communication in the CNS. AMPA-glutamate receptor (AMPAR) signaling governs the majority of excitatory synaptic activity in the mammalian brain. AMPAR activation in glioma cells activates cellular pathways that enhance proliferation and invasion and confer resistance to approved GB therapeutics. In addition, this review places a specific emphasis on discussing the redefined GB cytoarchitecture that consists of neuron-to-glioma cell synapses, whose oncogenic activity is driven by AMPAR activation on glioma cells, and the discovery of tumor microtubes, which propagate calcium signals throughout the tumor network in order to enhance resistance to complete surgical resection and radiotherapy. These new discoveries notwithstanding, some evidence suggests that AMPAR activation can produce excitotoxicity in tumor cells. This disparity warrants a closer examination at how AMPAR modulation can be leveraged to produce more durable outcomes in the treatment of GB and tumors in peripheral organs that express AMPAR. Full article

The Mojave rattlesnake venom shows significant geographical variability. The venom of Type A animals primarily contains β-neurotoxin referred to as Mojave Toxin (MTX), which makes bites from this snake particularly feared. We performed a genome-wide transcriptomic analysis of the neurocellular response to Mojave Type A rattlesnake venom using induced pluripotent stem cell-derived neural stem cells to unveil the molecular mechanisms underlying the damage caused by this snake’s envenomation. Our results suggest that snake venom metalloproteases, although having a limited repertoire in Type A venom, facilitate venom spread by digesting the tissue’s extracellular matrix. The MTX, which is composed of heterodimers of basic and acidic phospholipase-A2, co-opts the host arachidonic acid and Ca²⁺ second messenger mechanisms and triggers multiple signaling cascades, such as the activation of MAPKs and NF-κB-regulated proinflammatory genes; the neurotransmitter overload in excitatory synapses leading to a presynaptic blockade of nerve signals; and the upregulation of unfolded protein response (UPR) due to the depletion of Ca²⁺ from the endoplasmic reticulum. The upregulated UPR and the oxidative stress caused by reactive oxygen species generated in cytochromeP4501A1-mediated hydroxylation of arachidonic acid contribute to mitochondrial toxicity. The activation of UPR, mitochondrial toxicity, and oxidative stress synergistically contributed to apoptotic and ferroptotic cell death. Full article

Chimera states and bump states are collective synchronization phenomena observed independently (in different parameter regions) in networks of coupled nonlinear oscillators. And while chimera states are characterized by coexistence of coherent and incoherent domains, bump states consist of alternating active and inactive domains. The idea of multistable plasticity in the network connections originates from brain dynamics where the strength of the synapses (axons) connecting the network nodes (neurons) may change dynamically in time; when reaching the steady state the network connections may be found in one of many possible values depending on various factors, such as local connectivity, influence of neighboring cells etc. The sign of the link weights is also a significant factor in the network dynamics: positive weights are characterized as excitatory connections and negative ones as inhibitory. In the present study we consider the simplest case of bistable plasticity, where the link dynamics has only two fixed points. During the system/network integration, the link weights change and as a consequence the network organizes in excitatory or inhibitory domains characterized by different synaptic strengths. We specifically explore the influence of bistable plasticity on collective synchronization states and we numerically demonstrate that the dynamics of the linking may, under special conditions, give rise to co-existence of bump-like and chimera-like states simultaneously in the network. In the case of bump and chimera co-existence, confinement effects appear: the different domains stay localized and do not travel around the network. Memory effects are also reported in the sense that the final spatial arrangement of the coupling strengths reflects some of the local properties of the initial link distribution. For the quantification of the system’s spatial and temporal features, the global and local entropy functions are employed as measures of the network organization, while the average firing rates account for the network evolution and dynamics. In particular, the spatial minima of the local entropy designate the transition points between domains of different synaptic weights in the hybrid states, while the number of minima corresponds to the number of different domains. In addition, the entropy deviations signify the presence of chimera-like or bump-like states in the network. Full article

Background: Brain-inspired models are commonly employed for artificial intelligence. However, the complex environment can hinder the performance of electronic equipment. Therefore, enhancing the injury resistance of brain-inspired models is a crucial issue. Human brains have self-adaptive abilities under injury, so drawing on the advantages of the human brain to construct a brain-inspired model is intended to enhance its injury resistance. But current brain-inspired models still lack bio-plausibility, meaning they do not sufficiently draw on real neural systems’ structure or function. Methods: To address this challenge, this paper proposes the complex spiking neural network (Com-SNN) as a brain-inspired model, in which the topology is inspired by the topological characteristics of biological functional brain networks, the nodes are Izhikevich neuron models, and the edges are synaptic plasticity models with time delay co-regulated by excitatory synapses and inhibitory synapses. To evaluate the injury resistance of the Com-SNN, two injury-resistance metrics are investigated and compared with SNNs with alternative topologies under the stochastic removal of neuron models to simulate the consequence of stochastic attacks. In addition, the injury-resistance mechanism of brain-inspired models remains unclear, and revealing the mechanism is crucial for understanding the development of SNNs with injury resistance. To address this challenge, this paper analyzes the synaptic plasticity dynamic regulation and dynamic topological characteristics of the Com-SNN under stochastic attacks. Results: The experimental results indicate that the injury resistance of the Com-SNN is superior to that of other SNNs, demonstrating that our results can help improve the injury resistance of SNNs. Conclusions: Our results imply that synaptic plasticity is an intrinsic element impacting injury resistance, and that network topology is another element that impacts injury resistance. Full article

Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. In the DS brain, since the prenatal life stages, the number of astrocytes is disproportional compared to the healthy brain. This increase is due to a shift from neuron to astrocyte differentiation during brain development. Astrocytes are involved in numerous functions during brain development, including balancing pro-neurogenic and pro-gliogenic stimuli, sustaining synapse formation, regulating excitatory/inhibitory signal equilibrium, and supporting the maintenance and integration of functional neural circuits. The enhanced number of astrocytes in the brain of DS individuals leads to detrimental consequences for brain development. This review summarizes the mechanisms underlying astrocytic dysfunction in DS, and particularly the dysregulation of key signaling pathways, which promote astrogliogenesis at the expense of neurogenesis. It further examines the implications of astrocytic alterations on dendritic branching, spinogenesis and synaptogenesis, and the impact of the abnormal astrocytic number in neural excitability and in the maintenance of the inhibitory/excitatory balance. Identifying deregulated pathways and the consequences of astrocytic alterations in early DS brain development may help in identifying new therapeutic targets, with the ultimate aim of ameliorating the cognitive disability that affects individuals with DS. Full article