2-Ethylhexyl Diphenyl Phosphate Induces Autism Spectrum Disorder-Like Behaviors in Offspring Mice by Disrupting Postsynaptic Development.

As organophosphorus flame retardants (OPFRs) are constantly detected in human samples, the neurotoxicity of OPFRs is of concern. In this study, pregnant ICR mice were exposed to 2-ethylhexyl diphenyl phosphate (EHDPP) in drinking water from gestation to lactation to investigate its effects on autism spectrum disorder-like (ASD-like) behaviors in offspring. Serum EHDPP concentrations in dams in the 0.4, 2, and 10 mg/kg groups were 0.282 ± 0.051, 0.713 ± 0.115, and 0.974 ± 0.048 ng/mL, respectively, within the concentration range in humans. At the highest dose, EHDPP exposure induced ASD-like behaviors in both female and male offspring. Significant reductions in mature dendritic spines and structural damage to the postsynaptic density zone were noted in all but the lowest exposure groups, indicating postsynaptic membrane impairment. Mechanistically, EHDPP significantly downregulated disc large MAGUK scaffold protein 4 expression by inhibiting protein kinase B and type 1 insulin-like growth factor receptor phosphorylation. In the heterologous synapse formation assay in vivo, EHDPP significantly reduced the levels of postsynaptic density protein 95 expression in neurons at 1 µM. Overall, the study utilized in vitro and in vivo experiments to confirm that EHDPP damaged postsynaptic membrane formation and might increase the incidence of ASD in offspring.

Huanglian Jiedu decoction alleviates ischemia-induced cerebral injury in rats by mitigating NET formation and activiting GABAergic synapses.

Huanglian Jiedu decoction (HLJD) has been used to treat ischemic stroke in clinic. However, the detailed protective mechanisms of HLJD on ischemic stroke have yet to be elucidated. The aim of this study is to elucidate the underlying pharmacological mechanisms of HLJD based on the inhibition of neuroinflammation and the amelioration of nerve cell damage. A middle cerebral artery occlusion reperfusion (MCAO/R) model was established in rats and received HLJD treatment. Effects of HLJD on neurological function was assessed based on Bederson's score, postural reflex test and asymmetry score. 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining, Hematein and eosin (HE) and Nissl staining were used to observe the pathological changes in brain. Then, transcriptomics was used to screen the differential genes in brain tissue in MCAO/R model rats following HLJD intervention. Subsequently, the effects of HLJD on neutrophil extracellular trap (NET) formation-related neuroinflammation, gamma-aminobutyric acid (GABA)ergic synapse activation, nerve cell damage and proliferation were validated using immunofluorescence, western blot and enzyme-linked immunosorbent assay (ELISA). Our results showed that HLJD intervention reduced the Bederson's score, postural reflex test score and asymmetry score in MCAO/R model rats. Pathological staining indicated that HLJD treatment decreased the cerebral infarction area, mitigated neuronal damage and increased the numbers of Nissl bodies. Transcriptomics suggested that HLJD affected 435 genes in MCAO/R rats. Among them, several genes involving in NET formation and GABAergic synapses pathways were dysregulated. Subsequent experimental validation showed that HLJD reduced the MPO+CitH3+ positive expression area, reduced the protein expression of PAD4, p-P38/P38, p-ERK/ERK and decreased the levels of IL-1ß, IL-6 and TNF-α, reversed the increase of Iba1+TLR4+, Iba1+p65+ and Iba1+NLRP3+ positive expression area in brain. Moreover, HLJD increased GABA levels, elevated the protein expression of GABRG1 and GAT3, decreased the TUNEL positive expression area and increased the Ki67 positive expression area in brain. HLJD intervention exerts a multifaceted positive impact on ischemia-induced cerebral injury in MCAO/R rats. This intervention effectively inhibits neuroinflammation by mitigating NET formation, and concurrently improves nerve cell damage and fosters nerve cell proliferation through activating GABAergic synapses.

Performance Limits and Advancements in Single 2D Transition Metal Dichalcogenide Transistor.

Two-dimensional (2D) transition metal dichalcogenides (TMDs) allow for atomic-scale manipulation, challenging the conventional limitations of semiconductor materials. This capability may overcome the short-channel effect, sparking significant advancements in electronic devices that utilize 2D TMDs. Exploring the dimension and performance limits of transistors based on 2D TMDs has gained substantial importance. This review provides a comprehensive investigation into these limits of the single 2D-TMD transistor. It delves into the impacts of miniaturization, including the reduction of channel length, gate length, source/drain contact length, and dielectric thickness on transistor operation and performance. In addition, this review provides a detailed analysis of performance parameters such as source/drain contact resistance, subthreshold swing, hysteresis loop, carrier mobility, on/off ratio, and the development of p-type and single logic transistors. This review details the two logical expressions of the single 2D-TMD logic transistor, including current and voltage. It also emphasizes the role of 2D TMD-based transistors as memory devices, focusing on enhancing memory operation speed, endurance, data retention, and extinction ratio, as well as reducing energy consumption in memory devices functioning as artificial synapses. This review demonstrates the two calculating methods for dynamic energy consumption of 2D synaptic devices. This review not only summarizes the current state of the art in this field but also highlights potential future research directions and applications. It underscores the anticipated challenges, opportunities, and potential solutions in navigating the dimension and performance boundaries of 2D transistors.

Clec7a Worsens Long-Term Outcomes after Ischemic Stroke by Aggravating Microglia-Mediated Synapse Elimination.

Ischemic stroke (IS) is a leading cause of morbidity and mortality globally and triggers a series of reactions leading to primary and secondary brain injuries and permanent neurological deficits. Microglia in the central nervous system play dual roles in neuroprotection and responding to ischemic brain damage. Here, an IS model is employed to determine the involvement of microglia in phagocytosis at excitatory synapses. Additionally, the effects of pharmacological depletion of microglia are investigated on improving neurobehavioral outcomes and mitigating brain injury. RNA sequencing of microglia reveals an increase in phagocytosis-associated pathway activity and gene expression, and C-type lectin domain family 7 member A (Clec7a) is identified as a key regulator of this process. Manipulating microglial Clec7a expression can potentially regulate microglial phagocytosis of synapses, thereby preventing synaptic loss and improving neurobehavioral outcomes after IS. It is further demonstrat that microglial Clec7a interacts with neuronal myeloid differentiation protein 2 (MD2), a key molecule mediating poststroke neurological injury, and propose the novel hypothesis that MD2 is a ligand for microglial Clec7a. These findings suggest that microglial Clec7a plays a critical role in mediating synaptic phagocytosis in a mouse model of IS, suggesting that Clec7a may be a therapeutic target for IS.

Hydrogel-Based Artificial Synapses for Sustainable Neuromorphic Electronics.

Hydrogels find widespread applications in biomedicine because of their outstanding biocompatibility, biodegradability, and tunable material properties. Hydrogels can be chemically functionalized or reinforced to respond to physical or chemical stimulation, which opens up new possibilities in the emerging field of intelligent bioelectronics. Here, the state-of-the-art in functional hydrogel-based transistors and memristors is reviewed as potential artificial synapses. Within these systems, hydrogels can serve as semisolid dielectric electrolytes in transistors and as switching layers in memristors. These synaptic devices with volatile and non-volatile resistive switching show good adaptability to external stimuli for short-term and long-term synaptic memory effects, some of which are integrated into synaptic arrays as artificial neurons; although, there are discrepancies in switching performance and efficacy. By comparing different hydrogels and their respective properties, an outlook is provided on a new range of biocompatible, environment-friendly, and sustainable neuromorphic hardware. How potential energy-efficient information storage and processing can be achieved using artificial neural networks with brain-inspired architecture for neuromorphic computing is described. The development of hydrogel-based artificial synapses can significantly impact the fields of neuromorphic bionics, biometrics, and biosensing.

Serial Cerebrospinal Fluid Sampling Reveals Trajectories of Potential Synaptic Biomarkers in Early Stages of Alzheimer's Disease.

Background: Synaptic dysfunction is closely associated with cognitive function in Alzheimer's disease (AD), and is present already in an early stage of the disease. Objective: Using serial cerebrospinal fluid (CSF) sampling, we aimed to investigate slopes of CSF synaptic proteins, and their relation with cognition along the AD continuum. Methods: We included subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) (n = 50 amyloid-ß+ [A +], n = 50 A-) and 50 patients with AD dementia from the Amsterdam dementia cohort, with CSF at two time points (median[IQR] 2.1[1.4-2.7] years). We analyzed 17 synaptic proteins and neurofilament light (NfL). Using linear mixed models we assessed trajectories of protein levels, and associations with cognitive decline (repeated Mini-Mental State Examination). We used Cox regression models to assess predictive value of protein levels for progression to AD dementia. Results: At baseline most proteins showed increased levels in AD dementia compared to the other groups. In contrast NPTX2 levels were lower in AD dementia. Higher baseline levels of SNAP25, ß-syn, and 14-3-3 proteins were associated with faster cognitive decline (St.B[SE] -0.27[0.12] to -0.61[0.12]). Longitudinal analyses showed that SYT1 and NPTX levels decreased over time in AD dementia (st.B[SE] -0.10[0.04] to -0.15[0.05]) and SCD/MCI-A+ (St.B[SE] -0.07[0.03] to -0.12[0.03]), but not in SCD/MCI-A- (pinteraction < 0.05). Increase over time in NfL levels was associated with faster cognitive decline in AD dementia (St.B[SE] -1.75[0.58]), but not in the other groups (pinteraction < 0.05). Conclusions: CSF synaptic proteins showed different slopes over time, suggesting complex synaptic dynamics. High levels of especially SNAP-25 may have value for prediction of cognitive decline in early AD stages, while increase in NfL over time correlates better with cognitive decline in later stages.

2D Atomic-Molecular Heterojunctions toward Brainoid Applications.

Brainoid computing using 2D atomic crystals and their heterostructures, by emulating the human brain's remarkable efficiency and minimal energy consumption in information processing, poses a formidable solution to the energy-efficiency and processing speed constraints inherent in the von Neumann architecture. However, conventional 2D material based heterostructures employed in brainoid devices are beset with limitations, performance uniformity, fabrication intricacies, and weak interfacial adhesion, which restrain their broader application. The introduction of novel 2D atomic-molecular heterojunctions (2DAMH), achieved through covalent functionalization of 2D materials with functional molecules, ushers in a new era for brain-like devices by providing both stability and tunability of functionalities. This review chiefly delves into the electronic attributes of 2DAMH derived from the synergy of polymer materials with 2D materials, emphasizing the most recent advancements in their utilization within memristive devices, particularly their potential in replicating the functionality of biological synapses. Despite ongoing challenges pertaining to precision in modification, scalability in production, and the refinement of underlying theories, the proliferation of innovative research is actively pursuing solutions. These endeavors illuminate the vast potential for incorporating 2DAMH within brain-inspired intelligent systems, highlighting the prospect of achieving a more efficient and energy-conserving computing paradigm.

Volatile and Nonvolatile Programmable Iontronic Memristor with Lithium Imbued TiOx for Neuromorphic Computing Applications.

We demonstrate a lithium (Li) imbued TiOx iontronic device that exhibits synapse-like short-term plasticity behavior without requiring a forming process beforehand or a compliance current during switching. A solid-state electrolyte lithium phosphorus oxynitride (LiPON) behaves as the ion source, and the embedding and releasing of Li ions inside the cathodic like TiOx renders volatile conductance responses from the device and offers a natural platform for hardware simulating neuron functionalities. Besides, these devices possess high uniformity and great endurance as no conductive filaments are present. Different short-term pulse-based phenomena, including paired pulse facilitation, post-tetanic potentiation, and spike rate-dependent plasticity, were observed with self-relaxation characteristics. Based on the voltage excitation period, the time scale of the volatile memory can be tuned. Temperature measurement reveals the ion displacement-induced conductance channels become frozen below 220 K. In addition, the volatile analog devices can be configured into nonvolatile memory units with multibit storage capabilities after an electroforming process. Therefore, on the same platform, we can configure volatile units as nonlinear dynamic reservoirs for performing neuromorphic training and the nonvolatile units as the weight storage layer. We proceed to use voice recognition as an example with the tunable time constant relationship and obtain 94.4% accuracy with a minimal training data set. Thus, this iontronic platform can effectively process and update temporal information for reservoir and neuromorphic computing paradigms.

Amitriptyline protects afferent synapses in the cochlea against excitotoxic trauma in vitro.

Afferent synapses between inner hair cells (IHCs) and the type I spiral ganglion neurons (SGNs) in the cochlea provide over 95% of sensory signals for auditory perception in the brain. However, these afferent synapses are particularly vulnerable to damage, for example from excitotoxicity, and exposure to noise in the environment which often leads to noise-induced cochlear synaptopathy (NICS). In this study, we simulated excitotoxic trauma by incubating kainic acid, a non-desensitizing agonist for AMPA type glutamate receptors on cultured cochleae. The possible protective effects of amitriptyline against NICS were examined. We found that, in IHCs, amitriptyline reversed the decrease of Ca2+ current and exocytosis caused by excitotoxic trauma. In SGNs, amitriptyline promoted the recovery of neurite loss caused by excitotoxic trauma. Furthermore, we found that the protective effects of amitriptyline are likely mediated by suppressing apoptosis factors that were upregulated during excitotoxic trauma. In conclusion, our results suggest that amitriptyline could protect afferent synapses in the cochlea from NICS, making it a potential drug candidate for hearing protection.

Novel Two-Terminal Synapse/Neuron Based on an Antiferroelectric Hafnium Zirconium Oxide Device for Neuromorphic Computing.

Functionally diverse devices with artificial neuron and synapse properties are critical for neuromorphic systems. We present a two-terminal artificial leaky-integrate-fire (LIF) neuron based on 6 nm Hf0.1Zr0.9O2 (HZO) antiferroelectric (AFE) thin films and develop a synaptic device through work function (WF) engineering. LIF neuron characteristics, including integration, firing, and leakage, are achieved in W/HZO/W devices due to the accumulated polarization and spontaneous depolarization of AFE HZO films. By engineering the top electrode with asymmetric WFs, we found that Au/Ti/HZO/W devices exhibit synaptic weight plasticity, such as paired-pulse facilitation and long-term potentiation/depression, achieving >90% accuracy in digit recognition within constructed artificial neural network systems. These findings suggest that AFE HZO capacitor-based neurons and WF-engineered artificial synapses hold promise for constructing efficient spiking neuron networks and artificial neural networks, thereby advancing neuromorphic computing applications based on emerging AFE HZO devices.

Synapse Regulation.

Microglia are the resident immune cells of the brain. As such, they rapidly detect changes in normal brain homeostasis and accurately respond by fine-tuning in a tightly regulated manner their morphology, gene expression, and functional behavior. Depending on the nature of these changes, microglia can thicken and retract their processes, proliferate and migrate, release numerous signaling factors and compounds influencing neuronal physiology (e.g., cytokines and trophic factors), in addition to secreting proteases able to transform the extracellular matrix, and phagocytosing various types of cellular debris, etc. Because microglia also transform rapidly (on a time scale of minutes) during experimental procedures, studying these very special cells requires methods that are specifically non-invasive. The development of such methods has provided unprecedented insights into the roles of microglia during normal physiological conditions. In particular, transcranial two-photon in vivo imaging revealed that presumably "resting" microglia continuously survey the brain parenchyma with their highly motile processes, in addition to modulating their structural and functional interactions with neuronal circuits along the changes in neuronal activity and behavioral experience occurring throughout the lifespan. In this chapter, we will describe how surveillant microglia interact with synaptic elements and modulate the number, maturation, function, and plasticity of synapses in the healthy developing, mature, and aging brain, with consequences on neuronal activity, learning and memory, and the behavioral outcome.

Comprehensively Modulated Sub-Attojoule Operated Optoelectronic Synapses for Image Encryption and Inpainting.

High-performance optoelectronic synaptic transistors play a crucial role in developing and emulating artificial visual systems. However, due to the predominant use of single-structure material modulation in optimizing optoelectronic synapses, their energy consumption significantly trails behind that of electronic synapses by several orders of magnitude. Herein, polymer dielectric layers and optimized contact strategies are adopted to realize the ultralow consumption optoelectronic synapses. Integration of polyimide dielectric significantly enhances photogenerated charge carrier dissociation, leading to substantial improvements in photoresponsivity (1.5 × 106 A·W-1), photodetectivity (6.9 × 1012 Jones), and external quantum efficiency (4.0 × 108%). Additionally, optimized contact properties augment their appeal for ultralow energy consumption in optoelectronic synapse applications. Excitatory postsynaptic current is triggered at an incredibly low voltage of 5 µV and boosts an impressively low energy consumption of 0.05 aJ, ranking among the best-reported results in this field. Next, we demonstrate an integrated system combining the MoS2 optoelectronic synapses with a recurrent neural network enabling 100% accurate recognition of optical signals, particularly in scenarios with aJ-leveled energy consumption. Finally, an image encryption system has been developed, in which images are encrypted by photoelectronic conversion of synapse arrays with random voltage settings and decrypted according to the recurrent neural network-based accuracy. More importantly, once partially damaged images are encrypted, through the decryption image inpainting can be realized due to the high accuracy. The proposed innovative approach holds promise for advancing artificial intelligence applications with improved energy efficiency, information security, and computational capabilities.

On the Genesis and Unique Functions of Zinc Neuromodulation.

In addition to the essential structural and catalytic functions of zinc, evolution has adopted synaptic zinc as a neuromodulator. In the brain, synaptic zinc is released from primarily glutamatergic neurons, notably in the neocortex, hippocampus, amygdala, and auditory brainstem. In these brain areas, synaptic zinc is essential for neuronal and sensory processing fine-tuning. But what niche does zinc fill in neural signaling that other neuromodulators do not? Here we discuss the evolutionary history of zinc as a signaling agent and its eventual adoption as an essential neuromodulator in the mammalian brain. We then attempt to describe the roles that zinc has carved out of the vast and diverse landscape of neuromodulators.

The Neuroprotective Effect of Neural Cell Adhesion Molecule L1 in the Hippocampus of Aged Alzheimer's Disease Model Mice.

Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common form of dementia, causing the loss of cognitive function. Our previous study has shown, using a doubly mutated mouse model of AD (APP/PS1), that the neural adhesion molecule L1 directly binds amyloid peptides and decreases plaque load and gliosis when injected as an adeno-associated virus construct (AAV-L1) into APP/PS1 mice. In this study, we microinjected AAV-L1, using a Hamilton syringe, directly into the 3-month-old APP/PS1 mouse hippocampus and waited for a year until significant neurodegeneration developed. We stereologically counted the principal neurons and parvalbumin-positive interneurons in the hippocampus, estimated the density of inhibitory synapses around principal cells, and compared the AAV-L1 injection models with control injections of green fluorescent protein (AAV-GFP) and the wild-type hippocampus. Our results show that there is a significant loss of granule cells in the dentate gyrus of the APP/PS1 mice, which was improved by AAV-L1 injection, compared with the AAV-GFP controls (p < 0.05). There is also a generalized loss of parvalbumin-positive interneurons in the hippocampus of APP/PS1 mice, which is ameliorated by AAV-L1 injection, compared with the AAV-GFP controls (p < 0.05). Additionally, AAV-L1 injection promotes the survival of inhibitory synapses around the principal cells compared with AAV-GFP controls in all three hippocampal subfields (p < 0.01). Our results indicate that L1 promotes neuronal survival and protects the synapses in an AD mouse model, which could have therapeutic implications.

All-in-One 2D Molecular Crystal Optoelectronic Synapse for Polarization-Sensitive Neuromorphic Visual System.

Neuromorphic visual systems (NVSs) hold the potential to not only preserve but also enhance human visual capabilities. One such augmentation lies in harnessing polarization information from light reflected or scattered off surfaces like bees, which can disclose unique characteristics imperceptible to the human eyes. While creating polarization-sensitive optoelectronic synapses presents an intriguing avenue for equipping NVS with this capability, integrating functions like polarization sensitivity, photodetection, and synaptic operations into a singular device has proven challenging. This integration typically necessitates distinct functional components for each performance metric, leading to intricate fabrication processes and constraining overall performance. Herein, a pioneering linear polarized light sensitive synaptic organic phototransistor (OPT) based on 2D molecular crystals (2DMCs) with highly integrated, all-in-one functionality, is demonstrated. By leveraging the superior crystallinity and molecular thinness of 2DMC, the synaptic OPT exhibits comprehensive superior performance, including a linear dichroic ratio up to 3.85, a high responsivity of 1.47 × 104 A W-1, and the adept emulation of biological synapse functions. A sophisticated application in noncontact fingerprint detection achieves a 99.8% recognition accuracy, further highlights its potential. The all-in-one 2DMC optoelectronic synapse for polarization-sensitive NVS marks a new era for intelligent perception systems.

Rapid reorganization of serotonin projections and antidepressant response to 5-HT1A-biased agonist NLX-101 in fluoxetine-resistant cF1ko mice.

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) like fluoxetine remain a first-line treatment for major depression, but are effective in less than half of patients and can take 4-8 weeks to show results. In this study, we examined cF1ko mice with genetically induced upregulation of 5-HT1A autoreceptors that reduces 5-HT neuronal activity. These mice display anxiety- and depression-related behaviors that did not respond to chronic fluoxetine treatment. We examined treatment with NLX-101, a biased agonist that preferentially targets 5-HT1A heteroreceptors. By testing different doses of NLX-101, we found that a dose of 0.2 mg/kg was effective in reducing depression-related behavior in cF1ko mice without causing hypothermia, a 5-HT1A autoreceptor-mediated response. After one hour, this dose activated dorsal raphe 5-HT neurons and cells in the medial prefrontal cortex (mPFC), increasing nuclear c-fos labelling in cF1ko mice. In cF1ko mice but not wild-type littermates, 0.2 mg/kg NLX-101 administered one hour prior to each behavioral test for two weeks reduced depressive behavior in the forced swim test, but increased anxiety-related behaviors in the open field, elevated plus maze, and novelty suppressed feeding tests. During this treatment, NLX-101 induced widespread increases in the density of 5-HT axons, varicosities, and especially synaptic and triadic structures, particularly in depression-related brain regions including mPFC, hippocampal CA1 and CA2/3, amygdala and nucleus accumbens of cF1ko mice. Overall, NLX-101 was rapid and effective in reducing depressive behavior in SSRI-resistant mice, but also induced anxiety-related behaviors. The increase in serotonin innervation induced by intermittent NLX-101 may contribute to its behavioral actions.

Increased excitatory connectivity and epileptiform activity in thrombospondin1/2 knockout mice following cortical trauma.

Thrombospondins (TSPs) are astrocyte-secreted extracellular matrix proteins that play key roles as regulators of synaptogenesis in the central nervous system. We previously showed that TSP1/2 are upregulated in the partial neocortical isolation model ("undercut" or "UC" below) of posttraumatic epileptogenesis and may contribute to abnormal axonal sprouting, aberrant synaptogenesis and epileptiform discharges in the UC cortex. These results led to the hypothesis that posttraumatic epileptogeneis would be reduced in TSP1/2 knockout (TSP1/2 KO) mice. To test the hypothesis, we made UC lesions at P21, and subsequent experiments were conducted 14d later at P35. Ex vivo extracellular single or multi-electrode field potential recordings were obtained from layer V in cortical slices at P35 and in vivo video-EEGs of spontaneous epileptiform bursts were recorded to examine the effect of TSP1/2 deletion on epileptogenesis following cortical injury. Immunohistochemical experiments were performed to assess the effect of TSP1/2 KO + UC on the number of putative excitatory synapses and the expression of TSP4 and HEVIN, other astrocytic proteins known to up-regulate excitatory synapse formation. Unexpectedly, our results showed that, compared with WT + UC mice, TSP1/2 KO + UC mice displayed increased epileptiform activity, as indicated by 1) increased incidence and more rapid propagation of evoked and spontaneous epileptiform discharges in UC neocortical slices; 2) increased occurrence of spontaneous epileptiform discharges in vivo. There was an associated increase in the density of VLUT1/PSD95-IR colocalizations (putative excitatory synapses) and significantly upregulated TSP4- and HEVIN-IR in TSP1/2 KO + UC versus WT + UC mice. Results suggest that TSP1/2 deletion plays a potential epileptogenic role following neocortical injury, associated with compensatory upregulation of TSP4 and HEVIN, which may contribute to the increase in the density of excitatory synapses and resulting neural network hyperexcitability.

High-Yield Production of Solution-Processed Highly Robust Organic Artificial Synapses by Thermal Treatments.

A promising approach for implementing biomimetic systems relies on organic electronic devices designed to emulate neural synapses. However, organic artificial synapses face challenges in achieving high yield and robustness, rendering them difficult to use in practical applications. In this work, a high-yield and highly stable bulk heterojunction (BHJ) synaptic device composed of Poly(3-hexylthiophene-2,5-diyl) (P3HT) and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) was fabricated via a simple solution process followed by thermal treatments. The crystallinity of P3HT and the precipitation of PCBM in BHJ films can be controlled by the thermal annealing temperatures. At 80 °C, P3HT reaches its highest crystallinity, while PCBM remains uniformly distributed. This thermal treatment significantly contributes to the fabrication of devices characterized by a high yield rate, reaching 98.43%. Additionally, this device remained operational even after being immersed in deionized water, ethanol, and seawater for 100 h. More importantly, it exhibited high elasticity over a wide temperature range from -90 to 310 °C. Finally, this device was utilized to construct a biomimetic vehicle with autonomous memory learning capabilities. After repeated training, the avoidance time was optimized by 31.4%. The robust P3HT:PCBM artificial synapses hold great promise for advancing the development of biomimetic electronic products in extreme environments.

Age-related alterations in efferent medial olivocochlear-outer hair cell and primary auditory ribbon synapses in CBA/J mice.

Introduction: Hearing decline stands as the most prevalent single sensory deficit associated with the aging process. Giving compelling evidence suggesting a protective effect associated with the efferent auditory system, the goal of our study was to characterize the age-related changes in the number of efferent medial olivocochlear (MOC) synapses regulating outer hair cell (OHC) activity compared with the number of afferent inner hair cell ribbon synapses in CBA/J mice over their lifespan. Methods: Organs of Corti of 3-month-old CBA/J mice were compared with mice aged between 10 and 20 months, grouped at 2-month intervals. For each animal, one ear was used to characterize the synapses between the efferent MOC fibers and the outer hair cells (OHCs), while the contralateral ear was used to analyze the ribbon synapses between inner hair cells (IHCs) and type I afferent nerve fibers of spiral ganglion neurons (SGNs). Each cochlea was separated in apical, middle, and basal turns, respectively. Results: The first significant age-related decline in afferent IHC-SGN ribbon synapses was observed in the basal cochlear turn at 14 months, the middle turn at 16 months, and the apical turn at 18 months of age. In contrast, efferent MOC-OHC synapses in CBA/J mice exhibited a less pronounced loss due to aging which only became significant in the basal and middle turns of the cochlea by 20 months of age. Discussion: This study illustrates an age-related reduction on efferent MOC innervation of OHCs in CBA/J mice starting at 20 months of age. Our findings indicate that the morphological decline of efferent MOC-OHC synapses due to aging occurs notably later than the decline observed in afferent IHC-SGN ribbon synapses.

Association of connexin36 with adherens junctions at mixed synapses and distinguishing electrophysiological features of those at mossy fiber terminals in rat ventral hippocampus.

BACKGROUND: Granule cells in the hippocampus project axons to hippocampal CA3 pyramidal cells where they form large mossy fiber terminals. We have reported that these terminals contain the gap junction protein connexin36 (Cx36) specifically in the stratum lucidum of rat ventral hippocampus, thus creating morphologically mixed synapses that have the potential for dual chemical/electrical transmission. METHODOLOGY: Here, we used various approaches to characterize molecular and electrophysiological relationships between the Cx36-containing gap junctions at mossy fiber terminals and their postsynaptic elements and to examine molecular relationships at mixed synapses in the brainstem. RESULTS: In rat and human ventral hippocampus, many of these terminals, identified by their selective expression of vesicular zinc transporter-3 (ZnT3), displayed multiple, immunofluorescent Cx36-puncta representing gap junctions, which were absent at mossy fiber terminals in the dorsal hippocampus. In rat, these were found in close proximity to the protein constituents of adherens junctions (i.e., N-cadherin and nectin-1) that are structural hallmarks of mossy fiber terminals, linking these terminals to the dendritic shafts of CA3 pyramidal cells, thus indicating the loci of gap junctions at these contacts. Cx36-puncta were also associated with adherens junctions at mixed synapses in the brainstem, supporting emerging views of the structural organization of the adherens junction-neuronal gap junction complex. Electrophysiologically induced long-term potentiation (LTP) of field responses evoked by mossy fiber stimulation was greater in the ventral than dorsal hippocampus. CONCLUSIONS: The electrical component of transmission at mossy fiber terminals may contribute to enhanced LTP responses in the ventral hippocampus.