Multimodal sensory control of motor performance by glycinergic interneurons of the mouse spinal cord deep dorsal horn.

Sensory feedback is integral for contextually appropriate motor output, yet the neural circuits responsible remain elusive. Here, we pinpoint the medial deep dorsal horn of the mouse spinal cord as a convergence point for proprioceptive and cutaneous input. Within this region, we identify a population of tonically active glycinergic inhibitory neurons expressing parvalbumin. Using anatomy and electrophysiology, we demonstrate that deep dorsal horn parvalbumin-expressing interneuron (dPV) activity is shaped by convergent proprioceptive, cutaneous, and descending input. Selectively targeting spinal dPVs, we reveal their widespread ipsilateral inhibition onto pre-motor and motor networks and demonstrate their role in gating sensory-evoked muscle activity using electromyography (EMG) recordings. dPV ablation altered limb kinematics and step-cycle timing during treadmill locomotion and reduced the transitions between sub-movements during spontaneous behavior. These findings reveal a circuit basis by which sensory convergence onto dorsal horn inhibitory neurons modulates motor output to facilitate smooth movement and context-appropriate transitions.

Mapping the neuroethological signatures of pain, analgesia, and recovery in mice.

Ongoing pain is driven by the activation and modulation of pain-sensing neurons, affecting physiology, motor function, and motivation to engage in certain behaviors. The complexity of the pain state has evaded a comprehensive definition, especially in non-verbal animals. Here, in mice, we used site-specific electrophysiology to define key time points corresponding to peripheral sensitivity in acute paw inflammation and chronic knee pain models. Using supervised and unsupervised machine learning tools, we uncovered sensory-evoked coping postures unique to each model. Through 3D pose analytics, we identified movement sequences that robustly represent different pain states and found that commonly used analgesics do not return an animal's behavior to a pre-injury state. Instead, these analgesics induce a novel set of spontaneous behaviors that are maintained even after resolution of evoked pain behaviors. Together, these findings reveal previously unidentified neuroethological signatures of pain and analgesia at heightened pain states and during recovery.

Wafer-scale heterogeneous integration of thin film lithium niobate on silicon-nitride photonic integrated circuits with low loss bonding interfaces.

Silicon nitride (Si3N4) is a versatile waveguide material platform for CMOS foundry-based photonic integrated circuits (PICs) with low loss and high-power handling. The range of applications enabled by this platform is significantly expanded with the addition of a material with large electro-optic and nonlinear coefficients such as lithium niobate. This work examines the heterogeneous integration of thin-film lithium-niobate (TFLN) on silicon-nitride PICs. Bonding approaches are evaluated based on the interface used (SiO2, Al2O3 and direct) to form hybrid waveguide structures. We demonstrate low losses in chip-scale bonded ring resonators of 0.4 dB/cm (intrinsic Q = 8.19 × 105). In addition, we are able to scale the process to demonstrate bonding of full 100-mm TFLN wafers to 200-mm Si3N4 PIC wafers with high layer transfer yield. This will enable future integration with foundry processing and process design kits (PDKs) for applications such as integrated microwave photonics and quantum photonics.

A computational passage-of-time model of the cerebellar Purkinje cell in eyeblink conditioning.

The cerebellar Purkinje cell controlling eyeblinks can learn, remember, and reproduce the interstimulus interval in a classical conditioning paradigm. Given temporally separated inputs, the cerebellar Purkinje cell learns to pause its tonic inhibition of a motor pathway with high temporal precision so that an overt blink occurs at the right time. Most models place the passage-of-time representation in upstream network effects. Yet, bypassing the upstream network and directly stimulating the Purkinje cell's pre-synaptic fibers during conditioning still causes acquisition of a well-timed response. Additionally, while network models are sensitive to variance in the temporal structure of probe stimulation, in vivo findings suggest that the acquired Purkinje cell response is not. Such findings motivate alternative approaches to modeling neural function. Here, we present a proof-of-principle model of the passage-of-time which is internal to the Purkinje cell and is invariant to probe structure. The model is consistent with puzzling findings, accurately recapitulates Purkinje cell firing during classical conditioning and makes testable electrophysiological predictions.

Quantitative properties of the creation and activation of a cell-intrinsic duration-encoding engram.

The engram encoding the interval between the conditional stimulus (CS) and the unconditional stimulus (US) in eyeblink conditioning resides within a small population of cerebellar Purkinje cells. CSs activate this engram to produce a pause in the spontaneous firing rate of the cell, which times the CS-conditional blink. We developed a Bayesian algorithm that finds pause onsets and offsets in the records from individual CS-alone trials. We find that the pause consists of a single unusually long interspike interval. Its onset and offset latencies and their trial-to-trial variability are proportional to the CS-US interval. The coefficient of variation (CoV = σ/µ) are comparable to the CoVs for the conditional eye blink. The average trial-to-trial correlation between the onset latencies and the offset latencies is close to 0, implying that the onsets and offsets are mediated by two stochastically independent readings of the engram. The onset of the pause is step-like; there is no decline in firing rate between the onset of the CS and the onset of the pause. A single presynaptic spike volley suffices to trigger the reading of the engram; and the pause parameters are unaffected by subsequent volleys. The Fano factors for trial-to-trial variations in the distribution of interspike intervals within the intertrial intervals indicate pronounced non-stationarity in the endogenous spontaneous spiking rate, on which the CS-triggered firing pause supervenes. These properties of the spontaneous firing and of the engram read out may prove useful in finding the cell-intrinsic, molecular-level structure that encodes the CS-US interval.

Differential Influence of Soluble Dietary Fibres on Intestinal and Hepatic Carbohydrate Response.

Refined foods are commonly depleted in certain bioactive components that are abundant in 'natural' (plant) foods. Identification and addition of these 'missing' bioactives in the diet is, therefore, necessary to counteract the deleterious impact of convenience food. In this study, multiomics approaches were employed to assess the addition of the popular supplementary soluble dietary fibers inulin and psyllium, both in isolation and in combination with a refined animal feed. A 16S rRNA sequencing and 1H NMR metabolomic investigation revealed that, whilst inulin mediated an increase in Bifidobacteria, psyllium elicited a broader microbial shift, with Parasutterella and Akkermansia being increased and Enterorhabdus and Odoribacter decreased. Interestingly, the combination diet benefited from both inulin and psyllium related microbial changes. Psyllium mediated microbial changes correlated with a reduction of glucose (R -0.67, -0.73, respectively, p < 0.05) and type 2 diabetes associated metabolites: 3-methyl-2-oxovaleric acid (R -0.72, -0.78, respectively, p < 0.05), and citrulline (R -0.77, -0.71, respectively, p < 0.05). This was in line with intestinal and hepatic carbohydrate response (e.g., Slc2a2, Slc2a5, Khk and Fbp1) and hepatic lipogenesis (e.g., Srebf1 and Fasn), which were significantly reduced under psyllium addition. Although established in the liver, the intestinal response associated with psyllium was absent in the combination diet, placing greater significance upon the established microbial, and subsequent metabolomic, shift. Our results therefore highlight the heterogeneity that exists between distinct dietary fibers in the context of carbohydrate uptake and metabolism, and supports psyllium containing combination diets, for their ability to negate the impact of a refined diet.

Chronic ingestion of Primex-Z, compared with other common fat sources, drives worse liver injury and enhanced susceptibility to bacterial infections.

OBJECTIVES: The aim of this study was to investigate putative different outcomes on the development of non-alcoholic fatty liver disease in mice using fat options regularly used in human nutrition. METHODS: Male C57BL/6 mice were fed a control diet, and four different high-fat diets (HFD: 40% calories from fat; Research Diet, Inc., New Brunswick, New Jersey, USA) for 16 and 30 wk. HFDs had different common fat sources, including trans-fat, non-trans-fat palm oil (Primex-Z), palm oil alone, and corn oil alone. Mice were sacrificed and samples were collected for analysis. RESULTS: Using an unprecedented combination of in vivo imaging with immunometabolic phenotyping, we revealed that a HFD induced a major increase in hepatic lipid droplet deposition compared with control mice, being significantly higher in Primex-Z-fed mice. All HFD mice had similar or less weight gain as control mice; however, Primex-Z ingestion led to a higher increase in adiposity index (~90% increase) compared with other fat sources. Gene expression of isolated liver immune cells revealed large changes in expression of several inflammatory pathways, which were also more elevated in Primex-Z-fed mice, including Tnf (~20-fold), Il1b (~60-fold), and Tgfb (2.5-fold). Immunophenotyping and in vivo analysis showed that the frequency of hepatic immune cells was also disturbed during different HFD contents, rendering not only Kupffer cell depletion, but also reduced bacterial arresting ability. CONCLUSION: Different fat dietary sources imprint different immune and metabolic effects in the liver during consumption of an HFD. The present data highlighted that Primex-Z-a novel non-trans-fat-is not only able to damage hepatocytes, but also to impair liver ability to clear blood-borne infections.

Differential Involvement of EEG Oscillatory Components in Sameness versus Spatial-Relation Visual Reasoning Tasks.

The development of deep convolutional neural networks (CNNs) has recently led to great successes in computer vision, and CNNs have become de facto computational models of vision. However, a growing body of work suggests that they exhibit critical limitations on tasks beyond image categorization. Here, we study one such fundamental limitation, concerning the judgment of whether two simultaneously presented items are the same or different (SD) compared with a baseline assessment of their spatial relationship (SR). In both human subjects and artificial neural networks, we test the prediction that SD tasks recruit additional cortical mechanisms which underlie critical aspects of visual cognition that are not explained by current computational models. We thus recorded electroencephalography (EEG) signals from human participants engaged in the same tasks as the computational models. Importantly, in humans the two tasks were matched in terms of difficulty by an adaptive psychometric procedure; yet, on top of a modulation of evoked potentials (EPs), our results revealed higher activity in the low ß (16-24 Hz) band in the SD compared with the SR conditions. We surmise that these oscillations reflect the crucial involvement of additional mechanisms, such as working memory and attention, which are missing in current feed-forward CNNs.

Imaging and immunometabolic phenotyping uncover changes in the hepatic immune response in the early phases of NAFLD.

BACKGROUND & AIMS: The precise determination of non-alcoholic fatty liver disease (NAFLD) onset is challenging. Thus, the initial hepatic responses to fat accumulation, which may be fundamental to our understanding of NAFLD evolution and clinical outcomes, are largely unknown. Herein, we chronologically mapped the immunologic and metabolic changes in the liver during the early stages of fatty liver disease in mice and compared this with human NAFLD samples. METHODS: Liver biopsies from patients with NAFLD (NAFLD activity score [NAS] 2-3) were collected for gene expression profiling. Mice received a high-fat diet for short periods to mimic initial steatosis and the hepatic immune response was investigated using a combination of confocal intravital imaging, gene expression, cell isolation, flow cytometry and bone marrow transplantation assays. RESULTS: We observed major immunologic changes in patients with NAS 2-3 and in mice in the initial stages of NAFLD. In mice, these changes significantly increased mortality rates upon drug-induced liver injury, as well as predisposing mice to bacterial infections. Moreover, deletion of Toll-like receptor 4 in liver cells dampened tolerogenesis, particularly in Kupffer cells, in the initial stages of dietary insult. CONCLUSION: The hepatic immune system acts as a sentinel for early and minor changes in hepatic lipid content, mounting a biphasic response upon dietary insult. Priming of liver immune cells by gut-derived Toll-like receptor 4 ligands plays an important role in liver tolerance in initial phases, but continuous exposure to insults may lead to damage and reduced ability to control infections. LAY SUMMARY: Fatty liver is a very common form of hepatic disease, leading to millions of cases of cirrhosis every year. Patients are often asymptomatic until becoming very sick. Therefore, it is important that we expand our knowledge of the early stages of disease pathogenesis, to enable early diagnosis. Herein, we show that even in the early stages of fatty liver disease, there are significant alterations in genes involved in the inflammatory response, suggesting that the hepatic immune system is disturbed even following minor and undetectable changes in liver fat content. This could have implications for the diagnosis and clinical management of fatty liver disease.

Choice of Laboratory Rodent Diet May Confound Data Interpretation and Reproducibility.

The reproducibility of experimental data is challenged by many factors in both clinical and preclinical research. In preclinical studies, several factors may be responsible, and diet is one variable that is commonly overlooked, especially by those not trained in nutrition. In particular, grain-based diets contain complex ingredients, each of which can provide multiple nutrients, non-nutrients, and contaminants, which may vary from batch to batch. Thus, even when choosing the same grain-based diet used in the past by others, its composition will likely differ. In contrast, purified diets contain refined ingredients that offer the ability to control the composition much more closely and maintain consistency from one batch to the next, while minimizing the presence of non-nutrients and contaminants. In this article, we provide several different examples or scenarios showing how the diet choice can alter data interpretation, potentially affecting reproducibility and knowledge gained within any given field of study.

Near-infrared optics of nanoparticles embedded silica thin films.

This work investigates experimentally the near-infrared optical properties of SiO2 thin film embedded with tungsten (W) nanoparticles at varying volume fractions. The samples are prepared by using the technique of magnetron sputtering. The formation and distribution of W nanoparticles are characterized using transmission electron microscopy, and the volume fraction of W nanoparticles is validated by Auger electron spectroscopy. Near- and mid-infrared diffuse reflectance measurements are conducted using Fourier transform infrared spectroscopy. The samples exhibit wavelength selective optical response in the near-infrared region and are suitable for applications involving selective thermal emitters/absorbers. Measured reflectance data is utilized to estimate the effective dielectric function of the nano-composites. Calculated reflectance spectra in different samples are compared to the measured spectra using the experimentally measured dielectric function of these samples in the near-infrared region. Reflectance spectra after thermal annealing at different temperature are compared to show how the thermal treatment affects the optical properties of samples. Optimized structures are proposed for thermal emitters and absorbers with different volume fractions of W nanoparticles.

Effects of Rodent Diet Choice and Fiber Type on Data Interpretation of Gut Microbiome and Metabolic Disease Research.

Poor diet reporting and improperly controlling laboratory animal diet continues to reduce our ability to interpret data effectively in animal studies. In order to make the best use of our resources and improve research transparency, proper reporting methods that include a diet design are essential to improving our understanding of the links between gut health and metabolic disease onset. This unit will focus on the importance of diet choice in laboratory animal studies, specifically as it relates to gut health, microbiome, and metabolic disease development. The two most commonly used diet types, grain-based (GB) diets, and purified ingredient diets, will each be described, with particular emphasis on their differences in dietary fiber. A further description of how these diet types and fiber can affect gut morphology and microbiota will be provided as well as how purified ingredient diets may be improved upon. © 2018 by John Wiley & Sons, Inc.

Not-So-CLEVR: learning same-different relations strains feedforward neural networks.

The advent of deep learning has recently led to great successes in various engineering applications. As a prime example, convolutional neural networks, a type of feedforward neural network, now approach human accuracy on visual recognition tasks like image classification and face recognition. However, here we will show that feedforward neural networks struggle to learn abstract visual relations that are effortlessly recognized by non-human primates, birds, rodents and even insects. We systematically study the ability of feedforward neural networks to learn to recognize a variety of visual relations and demonstrate that same-different visual relations pose a particular strain on these networks. Networks fail to learn same-different visual relations when stimulus variability makes rote memorization difficult. Further, we show that learning same-different problems becomes trivial for a feedforward network that is fed with perceptually grouped stimuli. This demonstration and the comparative success of biological vision in learning visual relations suggests that feedback mechanisms such as attention, working memory and perceptual grouping may be the key components underlying human-level abstract visual reasoning.

Strain-induced modulation of near-field radiative transfer.

In this theoretical study, we present a near-field thermal modulator that exhibits change in radiative heat transfer when subjected to mechanical stress/strain. The device has two terminals at different temperatures separated by vacuum: one fixed and one stretchable. The stretchable side contains one-dimensional grating. When subjected to mechanical strain, the effective optical properties of the stretchable side are affected upon deformation of the grating. This results in modulation of surface waves across the interfaces influencing near-field radiative heat transfer. We show that for a separation of 100 nm, it is possible to achieve 25% change in radiative heat transfer for a strain of 10%.

Correction to: The common use of improper control diets in diet-induced metabolic disease research confounds data interpretation: the fiber factor.

[This corrects the article DOI: 10.1186/s12986-018-0243-5.].

Near-field thermal rectification devices using phase change periodic nanostructure.

We theoretically analyze two near-field thermal rectification devices: a radiative thermal diode and a thermal transistor that utilize a phase change material to achieve dynamic control over heat flow by exploiting metal-insulator transition of VO2 near 341 K. The thermal analogue of electronic diode allows high heat flow in one direction while it restricts the heat flow when the polarity of temperature gradient is reversed. We show that with the introduction of 1-D rectangular grating, thermal rectification is dramatically enhanced in the near-field due to reduced tunneling of surface waves across the interfaces for negative polarity. The radiative thermal transistor also works around phase transition temperature of VO2 and controls heat flow. We demonstrate a transistor-like behavior wherein heat flow across the source and the drain can be greatly varied by making a small change in gate temperature.

The common use of improper control diets in diet-induced metabolic disease research confounds data interpretation: the fiber factor.

Diets used to induce metabolic disease are generally high in fat and refined carbohydrates and importantly, are usually made with refined, purified ingredients. However, researchers will often use a low fat grain-based (GB) diet containing unrefined ingredients as the control diet. Such a comparison between two completely different diet types makes it impossible to draw conclusions regarding the phenotypic differences driven by diet. While many compositional differences can account for this, one major difference that could have the greatest impact between GB and purified diets is the fiber content, both in terms of the level and composition. We will review recent data showing how fiber differences between GB diets and purified diets can significantly influence gut health and microbiota, which itself can affect metabolic disease development. Researchers need to consider the control diet carefully in order to make the best use of precious experimental resources.

Dynamic optical response of SU-8 upon UV treatment.

We report the optical properties of SU-8 in the mid-infrared (mid-IR) region before and after UV treatment. Samples consisted of SU-8 films of thickness ranging from 10 um to 157 um deposited on gold coated silicon substrates and were prepared using spin coating. Mid-IR diffuse reflectance measurements were conducted using Fourier transform infrared spectroscopy. Spectra measurements imply a change in optical properties of SU-8 upon exposure to UV and heat treatment. A gradual change in optical properties is seen after each step of UV treatment and the baking process. Reflectance spectra of thin-films were also observed to be thickness dependent. We calculate the dielectric function of SU-8 in the range 2 um to 15 um using the reflectance spectra of the samples.

Fiber-Mediated Nourishment of Gut Microbiota Protects against Diet-Induced Obesity by Restoring IL-22-Mediated Colonic Health.

Dietary supplementation with fermentable fiber suppresses adiposity and the associated parameters of metabolic syndrome. Microbiota-generated fiber-derived short-chain fatty acids (SCFAs) and free fatty acid receptors including GPR43 are thought to mediate these effects. We find that while fermentable (inulin), but not insoluble (cellulose), fiber markedly protected mice against high-fat diet (HFD)-induced metabolic syndrome, the effect was not significantly impaired by either inhibiting SCFA production or genetic ablation of GPR43. Rather, HFD decimates gut microbiota, resulting in loss of enterocyte proliferation, leading to microbiota encroachment, low-grade inflammation (LGI), and metabolic syndrome. Enriching HFD with inulin restored microbiota loads, interleukin-22 (IL-22) production, enterocyte proliferation, and antimicrobial gene expression in a microbiota-dependent manner, as assessed by antibiotic and germ-free approaches. Inulin-induced IL-22 expression, which required innate lymphoid cells, prevented microbiota encroachment and protected against LGI and metabolic syndrome. Thus, fermentable fiber protects against metabolic syndrome by nourishing microbiota to restore IL-22-mediated enterocyte function.

Supplementation of Low- and High-fat Diets with Fermentable Fiber Exacerbates Severity of DSS-induced Acute Colitis.

BACKGROUND: Lack of dietary fiber has been suggested to increase the risk of developing various chronic inflammatory diseases, whereas supplementation of diets with fiber might offer an array of health-promoting benefits. Consistent with this theme, we recently reported that in mice, compositionally defined diets that are made with purified ingredients and lack fermentable fiber promote low-grade inflammation and metabolic syndrome, both of which could be ameliorated by supplementation of such diets with the fermentable fiber inulin. METHODS: Herein, we examined if, relative to a grain-based mouse diet (chow), compositionally defined diet consumption would impact development of intestinal inflammation induced by dextran sulfate sodium (DSS) and moreover, whether DSS-induced colitis might also be attenuated by diets supplemented with inulin. RESULTS: Analogous to their promotion of low-grade inflammation, compositionally defined diet of high- and low-fat content with cellulose increased the severity of DSS-induced colitis relative to chow. However, in contrast to the case of low-grade inflammation, addition of inulin, but not the insoluble fiber cellulose, further exacerbated the severity of colitis and its associated clinical manifestations (weight loss and bleeding) in both low- and high-fat diets. CONCLUSIONS: While inulin, and perhaps other fermentable fibers, can ameliorate low-grade inflammation and associated metabolic disease, it also has the potential to exacerbate disease severity in response to inducers of acute colitis.