Border cells without theta rhythmicity in the medial prefrontal cortex.

The medial prefrontal cortex (mPFC) is a key brain structure for higher cognitive functions such as decision-making and goal-directed behavior, many of which require awareness of spatial variables including one's current position within the surrounding environment. Although previous studies have reported spatially tuned activities in mPFC during memory-related trajectory, the spatial tuning of mPFC network during freely foraging behavior remains elusive. Here, we reveal geometric border or border-proximal representations from the neural activity of mPFC ensembles during naturally exploring behavior, with both allocentric and egocentric boundary responses. Unlike most of classical border cells in the medial entorhinal cortex (MEC) discharging along a single wall, a large majority of border cells in mPFC fire particularly along four walls. mPFC border cells generate new firing fields to external insert, and remain stable under darkness, across distinct shapes, and in novel environments. In contrast to hippocampal theta entrainment during spatial working memory tasks, mPFC border cells rarely exhibited theta rhythmicity during spontaneous locomotion behavior. These findings reveal spatially modulated activity in mPFC, supporting local computation for cognitive functions involving spatial context and contributing to a broad spatial tuning property of cortical circuits.

Ice-Templated Synthesis of Atomic Cluster Cocatalyst with Regulable Coordination Number for Enhanced Photocatalytic Hydrogen Evolution.

Supported metal catalysts have been exploited in various applications. Among them, cocatalyst supported on photocatalyst is essential for activation of photocatalysis. However, cocatalyst decoration in a controllable fashion to promote intrinsic activity remains challenging. Herein, a versatile method is developed for cocatalyst synthesis using an ice-templating (ICT) strategy, resulting in size control from single-atom (SA), and atomic clusters (AC) to nanoparticles (NP). Importantly, the coordination numbers (CN) of decorated AC cocatalysts are highly controllable, and this ICT method applies to various metals and photocatalytic substrates. Taking narrow-band gap Ga-doped La5Ti2Cu0.9Ag0.1O7S5 (LTCA) photocatalyst as an example, supported Ru AC/LTCA catalysts with regulable Ru CNs have been prepared, delivering significantly enhanced activities compared to Ru SA and Ru NPs supported on LTCA. Specifically, Ru(CN = 3.4) AC/LTCA with an average CN of Ru─Ru bond measured to be ≈3.4 exhibits excellent photocatalytic H2 evolution rate (578 µmol h-1) under visible light irradiation. Density functional theory calculation reveals that the modeled Ru(CN = 3) atomic cluster cocatalyst possesses favorable electronic properties and available active sites for the H2 evolution reaction.

Densely populated tiny RuO2 crystallites supported by hierarchically porous carbon for full acidic water splitting.

The exploitation of highly active bifunctional electrocatalysts for the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) in acidic media has been a subject receiving immense interest. However, the existing catalysts usually suffer from low catalytic efficiency and poor corrosion resistance under acidic conditions. Herein, we report a facile molten salt method to fabricate ruthenium dioxide nanoparticles supported by hierarchically porous carbon (RuO2/PC) as a bifunctional electrocatalyst for full water splitting under strong acidic conditions. The formation of a densely populated nanocrystalline RuO2/carbon heterostructure helps expose catalytic sites, accelerates the mass transfer rate, and further enhances the acid resistance of RuO2 nanoparticles. The as-synthesized RuO2/PC consequently exhibits superior catalytic performance for the OER with an overpotential of 181 mV upon 10 mA cm-2 compared to that of the commercial RuO2 (343 mV) and a comparable performance to Pt/C for the HER (47.5 mV upon 10 mA cm-2) in 0.5 M H2SO4. The RuO2/PC shows promising stability with little degradation over ∼24 h. Impressively, the water electrolyzer based on RuO2/PC shows an overpotential of 326 mV at 10 mA cm-2, much lower than that of the electrolyzer based on the combination of Pt/C and RuO2 (400 mV), indicating its great potential towards practical application.

A Handheld Visible Resonance Raman Analyzer Used in Intraoperative Detection of Human Glioma.

There is still a lack of reliable intraoperative tools for glioma diagnosis and to guide the maximal safe resection of glioma. We report continuing work on the optical biopsy method to detect glioma grades and assess glioma boundaries intraoperatively using the VRR-LRRTM Raman analyzer, which is based on the visible resonance Raman spectroscopy (VRR) technique. A total of 2220 VRR spectra were collected during surgeries from 63 unprocessed fresh glioma tissues using the VRR-LRRTM Raman analyzer. After the VRR spectral analysis, we found differences in the native molecules in the fingerprint region and in the high-wavenumber region, and differences between normal (control) and different grades of glioma tissues. A principal component analysis-support vector machine (PCA-SVM) machine learning method was used to distinguish glioma tissues from normal tissues and different glioma grades. The accuracy in identifying glioma from normal tissue was over 80%, compared with the gold standard of histopathology reports of glioma. The VRR-LRRTM Raman analyzer may be a new label-free, real-time optical molecular pathology tool aiding in the intraoperative detection of glioma and identification of tumor boundaries, thus helping to guide maximal safe glioma removal and adjacent healthy tissue preservation.

Liquid Crystal Elastomer Based Dexterous Artificial Motor Unit.

Despite the great advancement in designing diverse soft robots, they are not yet as dexterous as animals in many aspects. One challenge is that they still lack the compact design of an artificial motor unit with a great comprehensive performance that can be conveniently fabricated, although many recently developed artificial muscles have shown excellent properties in one or two aspects. Herein, an artificial motor unit is developed based on gold-coated ultrathin liquid crystal elastomer (LCE) film. Subject to a voltage, Joule heating generated by the gold film increases the temperature of the LCE film underneath and causes it to contract. Due to the small thermal inertial and electrically controlling method of the ultrathin LCE structure, its cyclic actuation speed is fast and controllable. It is shown that under electrical stimulation, the actuation strain of the LCE-based motor unit reaches 45%, the strain rate reaches 750%/s, and the output power density is as high as 1360 W kg-1 . It is further demonstrated that the LCE-based motor unit behaves like an actuator, a brake, or a nonlinear spring on demand, analogous to most animal muscles. Finally, as a proof-of-concept, multiple highly dexterous artificial neuromuscular systems are demonstrated using the LCE-based motor unit.

Excitatory-inhibitory recurrent dynamics produce robust visual grids and stable attractors.

Spatially modulated grid cells have been recently found in the rat secondary visual cortex (V2) during active navigation. However, the computational mechanism and functional significance of V2 grid cells remain unknown. To address the knowledge gap, we train a biologically inspired excitatory-inhibitory recurrent neural network to perform a two-dimensional spatial navigation task with multisensory input. We find grid-like responses in both excitatory and inhibitory RNN units, which are robust with respect to spatial cues, dimensionality of visual input, and activation function. Population responses reveal a low-dimensional, torus-like manifold and attractor. We find a link between functional grid clusters with similar receptive fields and structured excitatory-to-excitatory connections. Additionally, multistable torus-like attractors emerged with increasing sparsity in inter- and intra-subnetwork connectivity. Finally, irregular grid patterns are found in recurrent neural network (RNN) units during a visual sequence recognition task. Together, our results suggest common computational mechanisms of V2 grid cells for spatial and non-spatial tasks.

Are Grid-Like Representations a Component of All Perception and Cognition?

Grid cells or grid-like responses have been reported in the rodent, bat and human brains during various spatial and non-spatial tasks. However, the functions of grid-like representations beyond the classical hippocampal formation remain elusive. Based on accumulating evidence from recent rodent recordings and human fMRI data, we make speculative accounts regarding the mechanisms and functional significance of the sensory cortical grid cells and further make theory-driven predictions. We argue and reason the rationale why grid responses may be universal in the brain for a wide range of perceptual and cognitive tasks that involve locomotion and mental navigation. Computational modeling may provide an alternative and complementary means to investigate the grid code or grid-like map. We hope that the new discussion will lead to experimentally testable hypotheses and drive future experimental data collection.

Sharp Tuning of Head Direction and Angular Head Velocity Cells in the Somatosensory Cortex.

Head direction (HD) cells form a fundamental component in the brain's spatial navigation system and are intricately linked to spatial memory and cognition. Although HD cells have been shown to act as an internal neuronal compass in various cortical and subcortical regions, the neural substrate of HD cells is incompletely understood. It is reported that HD cells in the somatosensory cortex comprise regular-spiking (RS, putative excitatory) and fast-spiking (FS, putative inhibitory) neurons. Surprisingly, somatosensory FS HD cells fire in bursts and display much sharper head-directionality than RS HD cells. These FS HD cells are nonconjunctive, rarely theta rhythmic, sparsely connected and enriched in layer 5. Moreover, sharply tuned FS HD cells, in contrast with RS HD cells, maintain stable tuning in darkness; FS HD cells' coexistence with RS HD cells and angular head velocity (AHV) cells in a layer-specific fashion through the somatosensory cortex presents a previously unreported configuration of spatial representation in the neocortex. Together, these findings challenge the notion that FS interneurons are weakly tuned to sensory stimuli, and offer a local circuit organization relevant to the generation and transmission of HD signaling in the brain.

Intraoperative detection of human meningioma using a handheld visible resonance Raman analyzer.

To report for the first time the preliminary results for the evaluation of a VRR-LRR™ analyzer based on visible resonance Raman technique to identify human meningioma grades and margins intraoperatively. Unprocessed primary and recurrent solid human meningeal tissues were collected from 33 patients and underwent Raman analysis during surgeries. A total of 1180 VRR spectra were acquired from fresh solid tissues using a VRR-LRR™ analyzer. A confocal HR Evolution (HORIBA, France SAS) Raman system with 532-nm excitation wavelength was also used to collect data for part of the ex vivo samples after they were thawed from - 80 °C for comparison. The preliminary analysis led to the following observations. (1) The intensity ratio of VRR peaks of protein to fatty acid (I2934/I2888) decreased with the increase of meningioma grade. (2) The ratio of VRR peaks of phosphorylated protein to amid I (I1588/I1639) decreased for the higher grade of meningioma. (3) Three RR vibration modes at 1378, 3174, and 3224 cm-1 which were related to the molecular vibrational bands of oxy-hemeprotein, amide B, and amide A protein significantly changed in peak intensities in the two types of meningioma tissues compared to normal tissue. (4) The changes in the intensities of VRR modes of carotenoids at 1156 and 1524 cm-1 were also found in the meningioma boundary. The VRR-LRR™ analyzer demonstrates a new approach for label-free, rapid, and objective identification of primary human meningioma in quasi-clinical settings. The accuracy for detecting meningioma tissues using support vector machines (SVMs) was over 70% based on Raman peaks of key biomolecules and up to 100% using principal component analysis (PCA).

A novel somatosensory spatial navigation system outside the hippocampal formation.

Spatially selective firing of place cells, grid cells, boundary vector/border cells and head direction cells constitutes the basic building blocks of a canonical spatial navigation system centered on the hippocampal-entorhinal complex. While head direction cells can be found throughout the brain, spatial tuning outside the hippocampal formation is often non-specific or conjunctive to other representations such as a reward. Although the precise mechanism of spatially selective firing activity is not understood, various studies show sensory inputs, particularly vision, heavily modulate spatial representation in the hippocampal-entorhinal circuit. To better understand the contribution of other sensory inputs in shaping spatial representation in the brain, we performed recording from the primary somatosensory cortex in foraging rats. To our surprise, we were able to detect the full complement of spatially selective firing patterns similar to that reported in the hippocampal-entorhinal network, namely, place cells, head direction cells, boundary vector/border cells, grid cells and conjunctive cells, in the somatosensory cortex. These newly identified somatosensory spatial cells form a spatial map outside the hippocampal formation and support the hypothesis that location information modulates body representation in the somatosensory cortex. Our findings provide transformative insights into our understanding of how spatial information is processed and integrated in the brain, as well as functional operations of the somatosensory cortex in the context of rehabilitation with brain-machine interfaces.

Comparison of Doxycycline and Benzathine Penicillin G for the Treatment of Early Syphilis.

Doxycycline is the preferred recommended second-line treatment for the treatment of early syphilis. Recent reports showed a declining efficacy trend of doxycycline in treatment of early syphilis. The aim of our study was to assess the serological response to the treatment for early syphilis with doxycycline compared with benzathine penicillin G and evaluate whether doxycycline is still an effective agent for the treatment of early syphilis. A record-based retrospective study was conducted. Patients were diagnosed with early syphilis in an sexually transmitted disease (STD) clinic from January 1, 2008 to December 31, 2014. They were treated with a single dose of benzathine penicillin G 2.4MU or oral doxycycline 100 mg twice daily for 14 days. Pearson's chi-squared test was used for data analysis. 601 cases were included in the final study sample: 105 (17.5%) patients received a 14-day course of doxycycline (doxycycline group), and 496 (82.5%) patients received single-dose benzathine penicillin G (BPG group). The serological responses at 6 months and 12 months after treatment were compared. No statistically significant differences were found between the two groups at 6 months (69.52% vs. 75.00%, P=0.245), and at 12 months (92.38% vs. 96.17%, P=0.115). Doxycycline is still an effective agent for the treatment of early syphilis.

A prefrontal-thalamo-hippocampal circuit for goal-directed spatial navigation.

Spatial navigation requires information about the relationship between current and future positions. The activity of hippocampal neurons appears to reflect such a relationship, representing not only instantaneous position but also the path towards a goal location. However, how the hippocampus obtains information about goal direction is poorly understood. Here we report a prefrontal-thalamic neural circuit that is required for hippocampal representation of routes or trajectories through the environment. Trajectory-dependent firing was observed in medial prefrontal cortex, the nucleus reuniens of the thalamus, and the CA1 region of the hippocampus in rats. Lesioning or optogenetic silencing of the nucleus reuniens substantially reduced trajectory-dependent CA1 firing. Trajectory-dependent activity was almost absent in CA3, which does not receive nucleus reuniens input. The data suggest that projections from medial prefrontal cortex, via the nucleus reuniens, are crucial for representation of the future path during goal-directed behaviour and point to the thalamus as a key node in networks for long-range communication between cortical regions involved in navigation.

Magnetogenetics: remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor.

Current neuromodulation techniques such as optogenetics and deep-brain stimulation are transforming basic and translational neuroscience. These two neuromodulation approaches are, however, invasive since surgical implantation of an optical fiber or wire electrode is required. Here, we have invented a non-invasive magnetogenetics that combines the genetic targeting of a magnetoreceptor with remote magnetic stimulation. The non-invasive activation of neurons was achieved by neuronal expression of an exogenous magnetoreceptor, an iron-sulfur cluster assembly protein 1 (Isca1). In HEK-293 cells and cultured hippocampal neurons expressing this magnetoreceptor, application of an external magnetic field resulted in membrane depolarization and calcium influx in a reproducible and reversible manner, as indicated by the ultrasensitive fluorescent calcium indicator GCaMP6s. Moreover, the magnetogenetic control of neuronal activity might be dependent on the direction of the magnetic field and exhibits on-response and off-response patterns for the external magnetic field applied. The activation of this magnetoreceptor can depolarize neurons and elicit trains of action potentials, which can be triggered repetitively with a remote magnetic field in whole-cell patch-clamp recording. In transgenic Caenorhabditis elegans expressing this magnetoreceptor in myo-3-specific muscle cells or mec-4-specific neurons, application of the external magnetic field triggered muscle contraction and withdrawal behavior of the worms, indicative of magnet-dependent activation of muscle cells and touch receptor neurons, respectively. The advantages of magnetogenetics over optogenetics are its exclusive non-invasive, deep penetration, long-term continuous dosing, unlimited accessibility, spatial uniformity and relative safety. Like optogenetics that has gone through decade-long improvements, magnetogenetics, with continuous modification and maturation, will reshape the current landscape of neuromodulation toolboxes and will have a broad range of applications to basic and translational neuroscience as well as other biological sciences. We envision a new age of magnetogenetics is coming.

Functional connectivity of the entorhinal-hippocampal space circuit.

The mammalian space circuit is known to contain several functionally specialized cell types, such as place cells in the hippocampus and grid cells, head-direction cells and border cells in the medial entorhinal cortex (MEC). The interaction between the entorhinal and hippocampal spatial representations is poorly understood, however. We have developed an optogenetic strategy to identify functionally defined cell types in the MEC that project directly to the hippocampus. By expressing channelrhodopsin-2 (ChR2) selectively in the hippocampus-projecting subset of entorhinal projection neurons, we were able to use light-evoked discharge as an instrument to determine whether specific entorhinal cell groups--such as grid cells, border cells and head-direction cells--have direct hippocampal projections. Photoinduced firing was observed at fixed minimal latencies in all functional cell categories, with grid cells as the most abundant hippocampus-projecting spatial cell type. We discuss how photoexcitation experiments can be used to distinguish the subset of hippocampus-projecting entorhinal neurons from neurons that are activated indirectly through the network. The functional breadth of entorhinal input implied by this analysis opens up the potential for rich dynamic interactions between place cells in the hippocampus and different functional cell types in the entorhinal cortex (EC).

Superficially projecting principal neurons in layer V of medial entorhinal cortex in the rat receive excitatory retrosplenial input.

Principal cells in layer V of the medial entorhinal cortex (MEC) have a nodal position in the cortical-hippocampal network. They are the main recipients of hippocampal output and receive inputs from several cortical areas, including a prominent one from the retrosplenial cortex (RSC), likely targeting basal dendrites of layer V neurons. The latter project to extrahippocampal structures but also relay information to the superficial layers of MEC, closing the hippocampal-entorhinal loop. In the rat, we electrophysiologically and morphologically characterized RSC input into MEC and conclude that RSC provides an excitatory input to layer V pyramidal cells. Ultrastructural analyses of anterogradely labeled RSC projections showed that RSC axons in layer V of MEC form predominantly asymmetrical, likely excitatory, synapses on dendritic spines (90%) or shafts (8%), with 2% symmetrical, likely inhibitory, synapses on shafts and spines. The overall excitatory nature of the RSC input was confirmed by an optogenetic approach. Patterned laser stimulation of channelrhodopsin-expressing presynaptic RSC axons evoked exclusively EPSPs in recorded postsynaptic layer V cells. All responding layer V pyramidal cells had an axon extending toward the white matter. Half of these neurons also sent an axon to superficial layers. Confocal imaging of RSC synapses onto MEC layer V neurons shown to project superficially by way of retrogradely labeling from superficial layers confirmed that proximal dendrites of superficially projecting cells are among the targets of inputs from RSC. The excitatory RSC input thus interacts with both entorhinal-cortical and entorhinal-hippocampal circuits.

Optogenetic dissection of entorhinal-hippocampal functional connectivity.

We used a combined optogenetic-electrophysiological strategy to determine the functional identity of entorhinal cells with output to the place-cell population in the hippocampus. Channelrhodopsin-2 (ChR2) was expressed selectively in the hippocampus-targeting subset of entorhinal projection neurons by infusing retrogradely transportable ChR2-coding recombinant adeno-associated virus in the hippocampus. Virally transduced ChR2-expressing cells were identified in medial entorhinal cortex as cells that fired at fixed minimal latencies in response to local flashes of light. A large number of responsive cells were grid cells, but short-latency firing was also induced in border cells and head-direction cells, as well as cells with irregular or nonspatial firing correlates, which suggests that place fields may be generated by convergence of signals from a broad spectrum of entorhinal functional cell types.

Recurrent inhibitory circuitry as a mechanism for grid formation.

Grid cells in layer II of the medial entorhinal cortex form a principal component of the mammalian neural representation of space. The firing pattern of a single grid cell has been hypothesized to be generated through attractor dynamics in a network with a specific local connectivity including both excitatory and inhibitory connections. However, experimental evidence supporting the presence of such connectivity among grid cells in layer II is limited. Here we report recordings from more than 600 neuron pairs in rat entorhinal slices, demonstrating that stellate cells, the principal cell type in the layer II grid network, are mainly interconnected via inhibitory interneurons. Using a model attractor network, we demonstrate that stable grid firing can emerge from a simple recurrent inhibitory network. Our findings thus suggest that the observed inhibitory microcircuitry between stellate cells is sufficient to generate grid-cell firing patterns in layer II of the medial entorhinal cortex.

Increasing levels of wild-type CREB up-regulates several activity-regulated inhibitor of death (AID) genes and promotes neuronal survival.

BACKGROUND: CREB (cAMP-response element binding protein) is the prototypical signal-regulated transcription factor. In neurons, it is the target of the synaptic activity-induced nuclear calcium-calcium/calmodulin dependent protein kinase (CaMK) IV signaling pathway that controls the expression of genes important for acquired neuroprotection as well as other long-lasting adaptive processes in the nervous system. The function of CREB as a transcriptional activator is controlled by its phosphorylation on serine 133, which can be catalyzed by CaMKIV and leads to the recruitment of the co-activator, CREB binding protein (CBP). Activation of CBP function by nuclear calcium-CaMKIV signaling is a second regulatory step required for CREB/CBP-mediated transcription. RESULTS: Here we used recombinant adeno-associated virus (rAAV) to increase the levels of wild type CREB or to overexpress a mutant version of CREB (mCREB) containing a serine to alanine mutation at position amino acid 133 in mouse hippocampal neurons. Increasing the levels of CREB was sufficient to boost neuroprotective activity even under basal conditions (i.e., in the absence of stimulation of synaptic activity). In contrast, overexpression of mCREB increased cell death. The ratio of phospho(serine 133)CREB to CREB immunoreactivity in unstimulated hippocampal neurons was similar for endogenous CREB and overexpressed wild type CREB and, as expected, dramatically reduced for overexpressed mCREB. A gene expression analysis revealed that increased expression of CREB but not that of mCREB in hippocampal neurons led to elevated expression levels of bdnf as well as that of several members of a previously characterized set of Activity-regulated Inhibitor of Death (AID) genes, which include atf3, btg2, gadd45ß, and gadd45γ. CONCLUSIONS: Our findings indicate that the expression levels of wild type CREB are a critical determinant of the ability of hippocampal neurons to survive harmful conditions. Increasing the levels of wild type CREB can, even without inducing synaptic activity, increase pro-survival gene expression and strengthen the neurons' neuroprotective shield. The observed degradation of CREB protein following NMDA treatment of hippocampal neurons suggests that the known CREB shut-off associated with extrasynaptic NMDA receptor-induced excitotoxicity is followed by CREB proteolysis.