Investigation and modulation of neural circuits in vivo at the cellular level are very important for studying functional connectivity in a brain. Recently, neural probes with stimulation capabilities ...have been introduced, and they provided an opportunity for studying neural activities at a specific region in the brain using various stimuli. However, previous methods have a limitation in dissecting long-range neural circuits due to inherent limitations on their designs. Moreover, the large size of the previously reported probes induces more significant tissue damage. Herein, we present a multifunctional multi-shank MEMS neural probe that is monolithically integrated with an optical waveguide for optical stimulation, microfluidic channels for drug delivery, and microelectrode arrays for recording neural signals from different regions at the cellular level. In this work, we successfully demonstrated the functionality of our probe by confirming and modulating the functional connectivity between the hippocampal CA3 and CA1 regions in vivo.
The FDA-approved small-molecule drug ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib inhibits Bruton's tyrosine kinase (BTK), a kinase ...involved in B cell receptor signaling. However, the potential regulation of neuroinflammatory responses in the brain by ibrutinib has not been comprehensively examined.
BV2 microglial cells were treated with ibrutinib (1 μM) or vehicle (1% DMSO), followed by lipopolysaccharide (LPS; 1 μg/ml) or PBS. RT-PCR, immunocytochemistry, and subcellular fractionation were performed to examine the effects of ibrutinib on neuroinflammatory responses. In addition, wild-type mice were sequentially injected with ibrutinib (10 mg/kg, i.p.) or vehicle (10% DMSO, i.p.), followed by LPS (10 mg/kg, i.p.) or PBS, and microglial and astrocyte activations were assessed using immunohistochemistry.
Ibrutinib significantly reduced LPS-induced increases in proinflammatory cytokine levels in BV2 microglial and primary microglial cells but not in primary astrocytes. Ibrutinib regulated TLR4 signaling to alter LPS-induced proinflammatory cytokine levels. In addition, ibrutinib significantly decreased LPS-induced increases in p-AKT and p-STAT3 levels, suggesting that ibrutinib attenuates LPS-induced neuroinflammatory responses by inhibiting AKT/STAT3 signaling pathways. Interestingly, ibrutinib also reduced LPS-induced BV2 microglial cell migration by inhibiting AKT signaling. Moreover, ibrutinib-injected wild-type mice exhibited significantly reduced microglial/astrocyte activation and COX-2 and IL-1β proinflammatory cytokine levels.
Our data provide insights on the mechanisms of a potential therapeutic strategy for neuroinflammation-related diseases.
Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABAA receptors by the tonically released GABA, resulting in a persistent GABAergic inhibitory action. It is one of ...the key regulators for neuronal excitability, exerting a powerful action on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic GABA release by genetic removal or pharmacological inhibition of Best1 or MAOB caused an enhanced neuronal excitability in cerebellar granule cells (GCs), synaptic transmission at the parallel fiber-Purkinje cell (PF-PC) synapses, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB resulted in a reduced neuronal excitability, synaptic transmission, and motor performance. The bidirectional modulation of astrocytic GABA by genetic alteration of Best1 or MAOB was confirmed by immunostaining and in vivo microdialysis. These findings indicate that astrocytes are the key player in motor coordination through tonic GABA release by modulating neuronal excitability and could be a good therapeutic target for various movement and psychiatric disorders, which show a disturbed excitation/inhibition balance.
This study reviews new pension accounting with K-IFRS and provides empirical changes in liability for retirement allowances with adoption of K-IFRS. It will help to understand the effect of pension ...accounting on individual firm’s financial report and the importance of public announcement of actuarial assumptions. Firms that adopted K-IFRS had various changes in retirement liability compared to the previous financial report not based on K-IFRS. Their actuarial assumptions for pension accounting should be announced, but only few of them were published. Data analysis shows that the small differences of the actuarial assumption may result in a big change of retirement related liability. Firms within IT industry also have similar behaviors, which means that additional financial regulations for pension accounting are recommended.
Low-intensity transcranial focused ultrasound stimulation is a promising candidate for noninvasive brain stimulation and accurate targeting of brain circuits because of its focusing capability and ...long penetration depth. However, achieving a sufficiently high spatial resolution to target small animal sub-regions is still challenging, especially in the axial direction.
To achieve high axial resolution, we designed a dual-crossed transducer system that achieved high spatial resolution in the axial direction without complex microfabrication, beamforming circuitry, and signal processing.
High axial resolution was achieved by crossing two ultrasound beams of commercially available piezoelectric curved transducers at the focal length of each transducer. After implementation of the fixture for the dual-crossed transducer system, three sets of in vivo animal experiments were conducted to demonstrate high target specificity of ultrasound neuromodulation using the dual-crossed transducer system (n = 38).
The full-width at half maximum (FWHM) focal volume of our dual-crossed transducer system was under 0.52 μm3. We report a focal diameter in both lateral and axial directions of 1 mm. To demonstrate successful in vivo brain stimulation of wild-type mice, we observed the movement of the forepaws. In addition, we targeted the habenula and verified the high spatial specificity of our dual-crossed transducer system.
Our results demonstrate the ability of the dual-crossed transducer system to target highly specific regions of mice brains using ultrasound stimulation. The proposed system is a valuable tool to study the complex neurological circuitry of the brain noninvasively.
•Crossing the beams of two ultrasound transducers dramatically reduced the axial diameter of the focal spot to 1 mm.•A 90°-angle crossing of the two ultrasound beams results in the most optimal and robust focal size.•The resulting 1 mm-diameter spherical focal spot is capable of targeting sub-regions of small animal brains.
A consolidated memory can be transiently destabilized by memory retrieval, after which memories are reconsolidated within a few hours; however, the molecular substrates underlying this ...destabilization process remain essentially unknown. Here we show that at lateral amygdala synapses, fear memory consolidation correlates with increased surface expression of calcium-impermeable AMPA receptors (CI-AMPARs), which are known to be more stable at the synapse, whereas memory retrieval induces an abrupt exchange of CI-AMPARs to calcium-permeable AMPARs (CP-AMPARs), which are known to be less stable at the synapse. We found that blockade of either CI-AMPAR endocytosis or NMDA receptor activity during memory retrieval, both of which blocked the exchange to CP-AMPARs, prevented memory destabilization, indicating that this transient exchange of AMPARs may underlie the transformation of a stable memory into an unstable memory. These newly inserted CP-AMPARs gradually exchanged back to CI-AMPARs within hours, which coincided with the course of reconsolidation. Furthermore, blocking the activity of these newly inserted CP-AMPARs after retrieval impaired reconsolidation, suggesting that they serve as synaptic “tags” that support synapse-specific reconsolidation. Taken together, our results reveal unexpected physiological roles of CI-AMPARs and CP-AMPARs in transforming a consolidated memory into an unstable memory and subsequently guiding reconsolidation.
According to a 2020 WHO study, cancer is responsible for one in every six fatalities. One in four patients die due to side effects and intolerance to chemotherapy, making it a leading cause of ...patient death. Compared to traditional tumor therapy, emerging treatment methods, including immunotherapy, gene therapy, photothermal therapy, and photodynamic therapy, have proven to be more effective. The aim of this review is to highlight the role of gold nanoparticles in advanced cancer treatment. A systematic and extensive literature review was conducted using the Web of Science, PubMed, EMBASE, Google Scholar, NCBI, and various websites. Highly relevant literature from 141 references was chosen for inclusion in this review. Recently, the synergistic benefits of nano therapy and cancer immunotherapy have been shown, which could allow earlier diagnosis, more focused cancer treatment, and improved disease control. Compared to other nanoparticles, the physical and optical characteristics of gold nanoparticles appear to have significantly greater effects on the target. It has a crucial role in acting as a drug carrier, biomarker, anti-angiogenesis agent, diagnostic agent, radiosensitizer, cancer immunotherapy, photodynamic therapy, and photothermal therapy. Gold nanoparticle-based cancer treatments can greatly reduce current drug and chemotherapy dosages.
Integration of stimulation modalities (e.g. electrical, optical, and chemical) on a large array of neural probes can enable an investigation of important underlying mechanisms of brain disorders that ...is not possible through neural recordings alone. Furthermore, it is important to achieve this integration of multiple functionalities in a compact structure to utilize a large number of the mouse models. Here we present a successful optical modulation of in vivo neural signals of a transgenic mouse through our compact 2D MEMS neural array (optrodes). Using a novel fabrication method that embeds a lower cladding layer in a silicon substrate, we achieved a thin silicon 2D optrode array that is capable of delivering light to multiple sites using SU-8 as a waveguide core. Without additional modification to the microelectrodes, the measured impedance of the multiple microelectrodes was below 1 MΩ at 1 kHz. In addition, with a low background noise level (± 25 μV), neural spikes from different individual neurons were recorded on each microelectrode. Lastly, we successfully used our optrodes to modulate the neural activity of a transgenic mouse through optical stimulation. These results demonstrate the functionality of the 2D optrode array and its potential as a next-generation tool for optogenetic applications.
This case study examined the reactions of local students to the diversity in student population. Specifically, it investigated how the local students' intercultural sensitivity to the international ...students is interrelated with their perception of the English-medium instruction (EMI) policy. The quantitative and qualitative analyses of the questionnaire responses of 213 college students and the subsequent interviews with 15 students revealed a lack of intercultural sensitivity which was correlated with their perception of EMI. The findings indicated that the local students' different perceptions of the policy interplayed, directly and indirectly, with their sensitivity to the cultures of international students. The implications of these findings are discussed in terms of cultivating intercultural sensitivity in an English as a lingua franca context. (HoF/text adopted).
Monoamine oxidase-B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer's disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in ...reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC
= 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.
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