Lateral inhibition in V1 controls neural & perceptual contrast sensitivity.

Lateral inhibition is a central principle for sensory system function. It is thought to operate by the activation of inhibitory neurons that restrict the spatial spread of sensory excitation. Much work on the role of inhibition in sensory systems has focused on visual cortex; however, the neurons, computations, and mechanisms underlying cortical lateral inhibition remain debated, and its importance for visual perception remains unknown. Here, we tested how lateral inhibition from PV or SST neurons in mouse primary visual cortex (V1) modulates neural and perceptual sensitivity to stimulus contrast. Lateral inhibition from PV neurons reduced neural and perceptual sensitivity to visual contrast in a uniform subtractive manner, whereas lateral inhibition from SST neurons more effectively changed the slope (or gain) of neural and perceptual contrast sensitivity. A neural circuit model identified spatially extensive lateral projections from SST neurons as the key factor, and we confirmed this with direct subthreshold measurements of a larger spatial footprint for SST versus PV lateral inhibition. Together, these results define cell-type specific computational roles for lateral inhibition in V1, and establish their unique consequences on sensitivity to contrast, a fundamental aspect of the visual world.

Narrowband gamma oscillations propagate and synchronize throughout the mouse thalamocortical visual system.

Oscillations of neural activity permeate sensory systems. In the visual system, broadband gamma oscillations (30-80 Hz) are thought to act as a communication mechanism underlying perception. However, these oscillations show widely varying frequency and phase, providing constraints for coordinating spike timing across areas. Here, we examined Allen Brain Observatory data and performed causal experiments to show that narrowband gamma (NBG) oscillations (50-70 Hz) propagate and synchronize throughout the awake mouse visual system. Lateral geniculate nucleus (LGN) neurons fired precisely relative to NBG phase in primary visual cortex (V1) and multiple higher visual areas (HVAs). NBG neurons across areas showed a higher likelihood of functional connectivity and stronger visual responses; remarkably, NBG neurons in LGN, preferring bright (ON) versus dark (OFF), fired at distinct NBG phases aligned across the cortical hierarchy. NBG oscillations may thus serve to coordinate spike timing across brain areas and facilitate communication of distinct visual features during perception.

Calcium imaging and analysis of the jugular-nodose ganglia enables identification of distinct vagal sensory neuron subsets.

Objective.Sensory nerves of the peripheral nervous system (PNS) transmit afferent signals from the body to the brain. These peripheral nerves are composed of distinct subsets of fibers and associated cell bodies, which reside in peripheral ganglia distributed throughout the viscera and along the spinal cord. The vagus nerve (cranial nerve X) is a complex polymodal nerve that transmits a wide array of sensory information, including signals related to mechanical, chemical, and noxious stimuli. To understand how stimuli applied to the vagus nerve are encoded by vagal sensory neurons in the jugular-nodose ganglia, we developed a framework for micro-endoscopic calcium imaging and analysis.Approach.We developed novel methods forin vivoimaging of the intact jugular-nodose ganglion using a miniature microscope (Miniscope) in transgenic mice with the genetically-encoded calcium indicator GCaMP6f. We adapted the Python-based analysis package Calcium Imaging Analysis (CaImAn) to process the resulting one-photon fluorescence data into calcium transients for subsequent analysis. Random forest classification was then used to identify specific types of neuronal responders.Results.We demonstrate that recordings from the jugular-nodose ganglia can be accomplished through careful surgical dissection and ganglia stabilization. Using a customized acquisition and analysis pipeline, we show that subsets of vagal sensory neurons respond to different chemical stimuli applied to the vagus nerve. Successful classification of the responses with a random forest model indicates that certain calcium transient features, such as amplitude and duration, are important for encoding these stimuli by sensory neurons.Significance.This experimental approach presents a new framework for investigating how individual vagal sensory neurons encode various stimuli on the vagus nerve. Our surgical and analytical approach can be applied to other PNS ganglia in rodents and other small animal species to elucidate previously unexplored roles for peripheral neurons in a diverse set of physiological functions.

High-frequency electrical stimulation attenuates neuronal release of inflammatory mediators and ameliorates neuropathic pain.

BACKGROUND: Neuroinflammation is an important driver of acute and chronic pain states. Therefore, targeting molecular mediators of neuroinflammation may present an opportunity for developing novel pain therapies. In preclinical models of neuroinflammatory pain, calcitonin gene-related peptide (CGRP), substance P and high mobility group box 1 protein (HMGB1) are molecules synthesized and released by sensory neurons which activate inflammation and pain. High-frequency electrical nerve stimulation (HFES) has achieved clinical success as an analgesic modality, but the underlying mechanism is unknown. Here, we reasoned that HFES inhibits neuroinflammatory mediator release by sensory neurons to reduce pain. METHODS: Utilizing in vitro and in vivo assays, we assessed the modulating effects of HFES on neuroinflammatory mediator release by activated sensory neurons. Dorsal root ganglia (DRG) neurons harvested from wildtype or transgenic mice expressing channelrhodopsin-2 (ChR2) were cultured on micro-electrode arrays, and effect of HFES on optogenetic- or capsaicin-induced neuroinflammatory mediator release was determined. Additionally, the effects of HFES on local neuroinflammatory mediator release and hyperalgesia was assessed in vivo using optogenetic paw stimulation and the neuropathic pain model of chronic constriction injury (CCI) of the sciatic nerve. RESULTS: Light- or capsaicin-evoked neuroinflammatory mediator release from cultured transgenic DRG sensory neurons was significantly reduced by concurrent HFES (10 kHz). In agreement with these findings, elevated levels of neuroinflammatory mediators were detected in the affected paw following optogenetic stimulation or CCI and were significantly attenuated using HFES (20.6 kHz for 10 min) delivered once daily for 3 days. CONCLUSION: These studies reveal a previously unidentified mechanism for the pain-modulating effect of HFES in the setting of acute and chronic nerve injury. The results support the mechanistic insight that HFES may reset sensory neurons into a less pro-inflammatory state via inhibiting the release of neuroinflammatory mediators resulting in reduced inflammation and pain.

Thalamic bursting and the role of timing and synchrony in thalamocortical signaling in the awake mouse.

The thalamus controls transmission of sensory signals from periphery to cortex, ultimately shaping perception. Despite this significant role, dynamic thalamic gating and the consequences for downstream cortical sensory representations have not been well studied in the awake brain. We optogenetically modulated the ventro-posterior-medial thalamus in the vibrissa pathway of the awake mouse and measured spiking activity in the thalamus and activity in primary somatosensory cortex (S1) using extracellular electrophysiology and genetically encoded voltage imaging. Thalamic hyperpolarization significantly enhanced thalamic sensory-evoked bursting; however, surprisingly, the S1 cortical response was not amplified, but instead, timing precision was significantly increased, spatial activation more focused, and there was an increased synchronization of cortical inhibitory neurons. A thalamocortical network model implicates the modulation of precise timing of feedforward thalamic population spiking, presenting a highly sensitive, timing-based gating of sensory signaling to the cortex.

China Pakistan Economic Corridor Digital Transformation.

The China-Pakistan Economic Corridor (CPEC) vision and mission are to improve the people's living standards of Pakistan and China through bilateral investments, trade, cultural exchanges, and economic activities. To achieve this envisioned dream, Pakistan established the China-Pakistan Economic Corridor Authority (CPECA) to further its completion, but Covid-19 slowed it down. This situation compelled the digitalization of CPEC. This article reviews the best practices and success stories of various digitalization and e-governance programs and, in this light, advises the implementation of the Ajman Digital Governance (ADG) model as a theoretical framework for CPEC digitalization. This article concludes that the Pakistani government needs to transform CPEC digitalization by setting up the CPEC Digitalization and Transformation Center (DTC) at the CPECA office to attract more investors and businesses.

Belt and Road Environmental Implications for South Asia.

The Belt and Road Initiative (BRI) can play a significant role in the sustainable development of South Asia if appropriately implemented. Apart from the economic, trade, and cultural benefits of this colossal infrastructure, less is known about its environmental impact on South Asia. This study looks closely at the potential impact of the BRI on the South Asian environment. This research is based on the government-issued environmental policies, peer-reviewed literature, media articles, and reports. It has been suggested that the BRI could have a negative impact on the South Asian environment, which provided if does not consider the Paris agreement with its partners in the region. The study suggests that partner countries should adopt the BRI project to the principles of environmental impact assessment.

Optimizing intact skull intrinsic signal imaging for subsequent targeted electrophysiology across mouse visual cortex.

Understanding brain function requires repeatable measurements of neural activity across multiple scales and multiple brain areas. In mice, large scale cortical neural activity evokes hemodynamic changes readily observable with intrinsic signal imaging (ISI). Pairing ISI with visual stimulation allows identification of primary visual cortex (V1) and higher visual areas (HVAs), typically through cranial windows that thin or remove the skull. These procedures can diminish long-term mechanical and physiological stability required for delicate electrophysiological measurements made weeks to months after imaging (e.g., in subjects undergoing behavioral training). Here, we optimized and directly validated an intact skull ISI system in mice. We first assessed how imaging quality and duration affect reliability of retinotopic maps in V1 and HVAs. We then verified ISI map retinotopy in V1 and HVAs with targeted, multi-site electrophysiology several weeks after imaging. Reliable ISI maps of V1 and multiple HVAs emerged with ~ 60 trials of imaging (65 ± 6 min), and these showed strong correlation to local field potential (LFP) retinotopy in superficial cortical layers (r2 = 0.74-0.82). This system is thus well-suited for targeted, multi-area electrophysiology weeks to months after imaging. We provide detailed instructions and code for other researchers to implement this system.

Development and evaluation of pH-sensitive biodegradable ternary blended hydrogel films (chitosan/guar gum/PVP) for drug delivery application.

pH responsive hydrogels have gained much attraction in biomedical fields. We have formulated ternary hydrogel films as a new carrier of drug. Polyelectrolyte complex of chitosan/guar gum/polyvinyl pyrrolidone cross-linked via sodium tripolyphosphate was developed by solution casting method. Fourier transform infrared spectroscopy, scanning electron microscopy and thermogravimetric analysis were conducted to examine the interactions between the polymeric chains, surface morphology and thermal stability, respectively. The swelling tests resulted that the swelling was reduced with the increase in the concentration of crosslinker due to the more entangled arrangement and less availability of pores in hydrogels. Ciprofloxacin hydrochloride was used as a model drug and its release in simulated gastric fluid, simulated intestinal fluid and phosphate buffer saline solution was studied. pH responsive behaviour of the hydrogels have subjected these hydrogels for drug release applications.

Probing mechanisms of visual spatial attention in mice.

The role of spatial attention for visual perception has been thoroughly studied in primates, but less so in mice. Several behavioral tasks in mice reveal spatial attentional effects, with similarities to observations in primates. Pairing these tasks with large-scale, cell-type-specific techniques could enable deeper access to underlying mechanisms, and help define the utility and limitations of resolving attentional effects on visual perception and neural activity in mice. In this Review, we evaluate behavioral and neural evidence for visual spatial attention in mice; assess how specializations of the mouse visual system and behavioral repertoire impact interpretation of spatial attentional effects; and outline how several measurement and manipulation techniques in mice could precisely test and refine models of attentional modulation across scales.

TiO2 Nanoparticle Filler-Based Mixed-Matrix PES/CA Nanofiltration Membranes for Enhanced Desalination.

Mixed-matrix nanocomposite (PES/CA/PVP) membranes were fabricated for water desalination by incorporating varying amount of titanium dioxide nanoparticles (TiO2 NPs) ranging from 0 and 2 wt. %. Efficient dispersion of nanoparticles within polymeric membranes was achieved using the chemical precipitation method for uniform surface generation, and an asymmetric morphology was achieved via phase inversion method. Finally, membranes were characterized by Fourier Transform Infrared (FTIR) spectroscopy, Thermo Gravimetric Analysis (TGA), Scanning Electron Microscopy (SEM), porosity and contact angle analysis. FTIR confirmed chemical composition of membranes in terms of polymers (PES/CA/PVP) and TiO2. TGA analysis confirmed an increase in thermal stability of membranes with the increase of TiO2 nanoparticles loading. The addition of TiO2 nanoparticles also resulted in an increase in porous structures due to an increase in mean pore size, as shown by SEM results. An increase in the hydrophilicity of the membranes was observed by increasing the concentration of TiO2 nanoparticles. The present study investigated pristine and mixed-matrix nanocomposite NF membrane performance while filtering a NaCl salt solution at varying concentration range (from 1 to 4 g/Lit 6 bar). The prepared membranes demonstrated significant improvement in water permeability and hydrophilicity. Further, to optimize the water flux and salt rejection, the concentration of Polyvinylpyrrolidone (PVP) was optimized along with TiO2 nanoparticles. Both the water flux and salt rejection of the fabricated membranes were observed to increase with an increase inTiO2 nanoparticles to 2 wt. % loading with optimized PVP concentration, which demonstrated the improved desalination performance of resultant membranes.

Spatial modulation of dark versus bright stimulus responses in the mouse visual system.

A fundamental task of the visual system is to respond to both increases and decreases of luminance with action potentials (ON and OFF responses1-4). OFF responses are stronger, faster, and more salient than ON responses in primary visual cortex (V1) of both cats5,6 and primates,7,8 but in ferrets9 and mice,10 ON responses can be stronger, weaker,11 or balanced12 in comparison to OFF responses. These discrepancies could arise from differences in species, experimental techniques, or stimulus properties, particularly retinotopic location in the visual field, as has been speculated;9 however, the role of retinotopy for ON/OFF dominance has not been systematically tested across multiple scales of neural activity within species. Here, we measured OFF versus ON responses across large portions of visual space with silicon probe and whole-cell patch-clamp recordings in mouse V1 and lateral geniculate nucleus (LGN). We found that OFF responses dominated in the central visual field, whereas ON and OFF responses were more balanced in the periphery. These findings were consistent across local field potential (LFP), spikes, and subthreshold membrane potential in V1, and were aligned with spatial biases in ON and OFF responses in LGN. Our findings reveal that retinotopy may provide a common organizing principle for spatial modulation of OFF versus ON processing in mammalian visual systems.

Effect of Varying Amount of Polyethylene Glycol (PEG-600) and 3-Aminopropyltriethoxysilane on the Properties of Chitosan based Reverse Osmosis Membranes.

Chitosan and polyethylene glycol (PEG-600) membranes were synthesized and crosslinked with 3-aminopropyltriethoxysilane (APTES). The main purpose of this research work is to synthesize RO membranes which can be used to provide desalinated water for drinking, industrial and agricultural purposes. Hydrogen bonding between chitosan and PEG was confirmed by displacement of the hydroxyl absorption peak at 3237 cm-1 in pure chitosan to lower values in crosslinked membranes by using FTIR. Dynamic mechanical analysis revealed that PEG lowers Tg of the modified membranes vs. pure chitosan from 128.5 °C in control to 120 °C in CS-PEG5. SEM results highlighted porous and anisotropic structure of crosslinked membranes. As the amount of PEG was increased, hydrophilicity of membranes was increased and water absorption increased up to a maximum of 67.34%. Permeation data showed that flux and salt rejection value of the modified membranes was increased up to a maximum of 80% and 40.4%, respectively. Modified films have antibacterial properties against Escherichia coli as compared to control membranes.

Diminished Cortical Excitation and Elevated Inhibition During Perceptual Impairments in a Mouse Model of Autism.

Sensory impairments are a core feature of autism spectrum disorder (ASD). These impairments affect visual perception and have been hypothesized to arise from imbalances in cortical excitatory and inhibitory activity. There is conflicting evidence for this hypothesis from several recent studies of transgenic mouse models of ASD; crucially, none have measured activity from identified excitatory and inhibitory neurons during simultaneous impairments of sensory perception. Here, we directly recorded putative excitatory and inhibitory population spiking in primary visual cortex (V1) while simultaneously measuring visual perceptual behavior in CNTNAP2-/- knockout (KO) mice. We observed quantitative impairments in the speed, accuracy, and contrast sensitivity of visual perception in KO mice. During these perceptual impairments, stimuli evoked more firing of inhibitory neurons and less firing of excitatory neurons, with reduced neural sensitivity to contrast. In addition, pervasive 3-10 Hz oscillations in superficial cortical layers 2/3 (L2/3) of KO mice degraded predictions of behavioral performance from neural activity. Our findings show that perceptual deficits relevant to ASD may be associated with elevated cortical inhibitory activity along with diminished and aberrant excitatory population activity in L2/3, a major source of feedforward projections to higher cortical regions.

Novel Maleic Acid, Crosslinked, Nanofibrous Chitosan/Poly (Vinylpyrrolidone) Membranes for Reverse Osmosis Desalination.

Fresh and clean water is consistently depleting and becoming a serious problem with rapid increases in population, so seawater desalination technology has captured global attention. For an efficient desalination process, this work proposes a novel, nanofibrous, thin-film composite membrane (NF-TFC) based on the deposition of the nanofibrous active layer of a blend of chitosan (CS) and poly (vinylpyrrolidone) (PVP) crosslinked with maleic acid on a 3-triethoxysilylpropylamine functionalized cellulose acetate substrate. FTIR analysis demonstrated the development of chemical and physical interactions and confirmed the incorporation of functional groups present in the NF-TFC. Scanning electron microscopy (SEM) micrographs depict the fibrous structure of the active layers. The reverse osmosis (RO) desalination characteristics of NF-TFC membranes are elevated by increasing the concentration of the crosslinker in a CS/PVP blend. Cellulose acetate (CA)-S4 attained an optimal salt rejection of 98.3% and permeation flux of 42.9 L/m2h, suggesting that the NF-TFC membranes could be favorable for seawater desalination.

Spatial attention enhances network, cellular and subthreshold responses in mouse visual cortex.

Internal brain states strongly modulate sensory processing during behaviour. Studies of visual processing in primates show that attention to space selectively improves behavioural and neural responses to stimuli at the attended locations. Here we develop a visual spatial task for mice that elicits behavioural improvements consistent with the effects of spatial attention, and simultaneously measure network, cellular, and subthreshold activity in primary visual cortex. During trial-by-trial behavioural improvements, local field potential (LFP) responses to stimuli detected inside the receptive field (RF) strengthen. Moreover, detection inside the RF selectively enhances excitatory and inhibitory neuron responses to task-irrelevant stimuli and suppresses noise correlations and low frequency LFP fluctuations. Whole-cell patch-clamp recordings reveal that detection inside the RF increases synaptic activity that depolarizes membrane potential responses at the behaviorally relevant location. Our study establishes that mice display fundamental signatures of visual spatial attention spanning behavioral, network, cellular, and synaptic levels, providing new insight into rapid cognitive enhancement of sensory signals in visual cortex.

Autonomous patch-clamp robot for functional characterization of neurons in vivo: development and application to mouse visual cortex.

Patch clamping is the gold standard measurement technique for cell-type characterization in vivo, but it has low throughput, is difficult to scale, and requires highly skilled operation. We developed an autonomous robot that can acquire multiple consecutive patch-clamp recordings in vivo. In practice, 40 pipettes loaded into a carousel are sequentially filled and inserted into the brain, localized to a cell, used for patch clamping, and disposed. Automated visual stimulation and electrophysiology software enables functional cell-type classification of whole cell-patched cells, as we show for 37 cells in the anesthetized mouse in visual cortex (V1) layer 5. We achieved 9% yield, with 5.3 min per attempt over hundreds of trials. The highly variable and low-yield nature of in vivo patch-clamp recordings will benefit from such a standardized, automated, quantitative approach, allowing development of optimal algorithms and enabling scaling required for large-scale studies and integration with complementary techniques. NEW & NOTEWORTHY In vivo patch-clamp is the gold standard for intracellular recordings, but it is a very manual and highly skilled technique. The robot in this work demonstrates the most automated in vivo patch-clamp experiment to date, by enabling production of multiple, serial intracellular recordings without human intervention. The robot automates pipette filling, wire threading, pipette positioning, neuron hunting, break-in, delivering sensory stimulus, and recording quality control, enabling in vivo cell-type characterization.

Cortical State Fluctuations across Layers of V1 during Visual Spatial Perception.

Many factors modulate the state of cortical activity, but the importance of cortical state variability for sensory perception remains debated. We trained mice to detect spatially localized visual stimuli and simultaneously measured local field potentials and excitatory and inhibitory neuron populations across layers of primary visual cortex (V1). Cortical states with low spontaneous firing and correlations in excitatory neurons, and suppression of 3- to 7-Hz oscillations in layer 4, accurately predicted single-trial visual detection. Our results show that cortical states exert strong effects at the initial stage of cortical processing in V1 and can play a prominent role for visual spatial behavior in mice.

A novel device for real-time measurement and manipulation of licking behavior in head-fixed mice.

The mouse has become an influential model system for investigating the mammalian nervous system. Technologies in mice enable recording and manipulation of neural circuits during tasks where they respond to sensory stimuli by licking for liquid rewards. Precise monitoring of licking during these tasks provides an accessible metric of sensory-motor processing, particularly when combined with simultaneous neural recordings. There are several challenges in designing and implementing lick detectors during head-fixed neurophysiological experiments in mice. First, mice are small, and licking behaviors are easily perturbed or biased by large sensors. Second, neural recordings during licking are highly sensitive to electrical contact artifacts. Third, submillisecond lick detection latencies are required to generate control signals that manipulate neural activity at appropriate time scales. Here we designed, characterized, and implemented a contactless dual-port device that precisely measures directional licking in head-fixed mice performing visual behavior. We first determined the optimal characteristics of our detector through design iteration and then quantified device performance under ideal conditions. We then tested performance during head-fixed mouse behavior with simultaneous neural recordings in vivo. We finally demonstrate our device's ability to detect directional licks and generate appropriate control signals in real time to rapidly suppress licking behavior via closed-loop inhibition of neural activity. Our dual-port detector is cost effective and easily replicable, and it should enable a wide variety of applications probing the neural circuit basis of sensory perception, motor action, and learning in normal and transgenic mouse models. NEW & NOTEWORTHY Mice readily learn tasks in which they respond to sensory cues by licking for liquid rewards; tasks that involve multiple licking responses allow study of neural circuits underlying decision making and sensory-motor integration. Here we design, characterize, and implement a novel dual-port lick detector that precisely measures directional licking in head-fixed mice performing visual behavior, enabling simultaneous neural recording and closed-loop manipulation of licking.

Subcortical Source and Modulation of the Narrowband Gamma Oscillation in Mouse Visual Cortex.

Primary visual cortex exhibits two types of gamma rhythm: broadband activity in the 30-90 Hz range and a narrowband oscillation seen in mice at frequencies close to 60 Hz. We investigated the sources of the narrowband gamma oscillation, the factors modulating its strength, and its relationship to broadband gamma activity. Narrowband and broadband gamma power were uncorrelated. Increasing visual contrast had opposite effects on the two rhythms: it increased broadband activity, but suppressed the narrowband oscillation. The narrowband oscillation was strongest in layer 4 and was mediated primarily by excitatory currents entrained by the synchronous, rhythmic firing of neurons in the lateral geniculate nucleus (LGN). The power and peak frequency of the narrowband gamma oscillation increased with light intensity. Silencing the cortex optogenetically did not abolish the narrowband oscillation in either LGN firing or cortical excitatory currents, suggesting that this oscillation reflects unidirectional flow of signals from thalamus to cortex.