The thalamic mGluR1-PLC??4 pathway is critical in sleep architecture

The transition from wakefulness to a nonrapid eye movement (NREM) sleep state at the onset of sleep involves a transition from low-voltage, high-frequency irregular electroencephalography (EEG) waveforms to large-amplitude, low-frequency EEG waveforms accompanying synchronized oscillatory activity in the thalamocortical circuit. The thalamocortical circuit consists of reciprocal connections between the thalamus and cortex. The cortex sends strong excitatory feedback to the thalamus, however the function of which is unclear. In this study, we investigated the role of the thalamic metabotropic glutamate receptor 1 (mGluR1)-phospholipase C ??4 (PLC??4) pathway in sleep control in PLC??4-deficient (PLC??4-/-) mice. The thalamic mGluR1-PLC??4 pathway contains synapses that receive corticothalamic inputs. In PLC??4-/- mice, the transition from wakefulness to the NREM sleep state was stimulated, and the NREM sleep state was stabilized, which resulted in increased NREM sleep. The power density of delta (??) waves increased in parallel with the increased NREM sleep. These sleep phenotypes in PLC??4-/- mice were consistent in TC-restricted PLC??4 knockdown mice. Moreover, in vitro intrathalamic oscillations were greatly enhanced in the PLC??4-/- slices. The results of our study showed that thalamic mGluR1-PLC??4 pathway was critical in controlling sleep architecture.ope

Sleep spindles are generated in the absence of T-type calcium channel-mediated low-threshold burst firing of thalamocortical neurons

T-type Ca2+ channels in thalamocortical (TC) neurons have long been considered to play a critical role in the genesis of sleep spindles, one of several TC oscillations. A classical model for TC oscillations states that reciprocal interaction between synaptically connected GABAergic thalamic reticular nucleus (TRN) neurons and glutamatergic TC neurons generates oscillations through Ttype channel-mediated low-threshold burst firings of neurons in the two nuclei. These oscillations are then transmitted from TC neurons to cortical neurons, contributing to the network of TC oscillations. Unexpectedly, however, we found that both WT and KO mice for CaV3.1, the gene for T-type Ca2+ channels in TC neurons, exhibit typical waxing-and-waning sleep spindle waves at a similar occurrence and with similar amplitudes and episode durations during non-rapid eye movement sleep. Single-unit recording in parallel with electroencephalography in vivo confirmed a complete lack of burst firing in the mutant TC neurons. Of particular interest, the tonic spike frequency in TC neurons was significantly increased during spindle periods compared with nonspindle periods in both genotypes. In contrast, no significant change in burst firing frequency between spindle and nonspindle periods was noted in the WT mice. Furthermore, spindle-like oscillations were readily generated within intrathalamic circuits composed solely of TRN and TC neurons in vitro in both the KO mutant and WT mice. Our findings call into question the essential role of low-threshold burst firings in TC neurons and suggest that tonic firing is important for the generation and propagation of spindle oscillations in the TC circuit.116141sciescopu

Mouse fMRI under ketamine and xylazine anesthesia: Robust contralateral somatosensory cortex activation in response to forepaw stimulation

Mouse fMRI is critically useful to investigate functions of mouse models. Until now, the somatosensory-evoked responses in anesthetized mice are often widespread and inconsistent across reports. Here, we adopted a ketamine and xylazine mixture for mouse fMRI, which is relatively new anesthetics in fMRI experiments. Forepaw stimulation frequency was optimized using cerebral blood volume (CBV)-weighted optical imaging (n = 11) and blood-oxygenation-level dependent (BOLD) fMRI with a gradient-echo time of 16 ms at 9.4 T, and 4 Hz stimulation with 0.5 ms and 0.5 mA pulses induced the highest hemodynamic response. For 20-s 4-Hz unilateral forepaw stimulation, localized BOLD activity was consistently found in the contralateral primary forelimb somatosensory cortex (S1FL), while no significant change was observed in the ipsilateral S1FL. The mean magnitude was 1.44 +/- 0.20% SEM (n = 9) in the contralateral S1FL and 0.69 +/- 0.10% in the contralateral thalamus. The variability of evoked fMRI responses across sessions was investigated by comparing with resting state fMRI (rsfMRI) functional connectivity (FC). Evoked responses in S1FL were correlated positively with rsfMRI FC between bilateral S1FL (r = 0.63 to 0.69) and negatively with FC between S1FL and the anterior cingulate cortex (r = -0.50 to -0.57), suggesting that rsfMRI FC is a good index of the evoked fMRI response and anesthetized animal condition. Finally, three weekly fMRI scans were performed in 5 mice, and localized activity was reproducibly observed in S1FL, with a success rate of 70-95%. In summary, our developed fMRI protocol can be used for mapping functions of mouse models.(NeuroImage 2018)(c) 2018 Elsevier Inc. All rights reserved

Covalent organic framework nanomedicines: Biocompatibility for advanced nanocarriers and cancer theranostics applications

Nanomedicines for drug delivery and imaging-guided cancer therapy is a rapidly growing research area. The unique properties of nanomedicines have a massive potential in solving longstanding challenges of existing cancer drugs, such as poor localization at the tumor site, high drug doses and toxicity, recurrence, and poor immune response. However, inadequate biocompatibility restricts their potential in clinical translation. Therefore, advanced nanomaterials with high biocompatibility and enhanced therapeutic efficiency are highly desired to fast-track the clinical translation of nanomedicines. Intrinsic properties of nanoscale covalent organic frameworks (nCOFs), such as suitable size, modular pore geometry and porosity, and straightforward post-synthetic modification via simple organic transformations, make them incredibly attractive for future nanomedicines. The ability of COFs to disintegrate in a slightly acidic tumor microenvironment also gives them a competitive advantage in targeted delivery. This review summarizes recently published applications of COFs in drug delivery, photo-immuno therapy, sonodynamic therapy, photothermal therapy, chemotherapy, pyroptosis, and combination therapy. Herein we mainly focused on modifications of COFs to enhance their biocompatibility, efficacy and potential clinical translation. This review will provide the fundamental knowledge in designing biocompatible nCOFs-based nanomedicines and will help in the rapid development of cancer drug carriers and theranostics