Articles

by Ryota Kondo, Yamato Tani, Maki Sugimoto, Kouta Minamizawa, Masahiko Inami and Michiteru Kitazaki Frontiers in Robotics and AI.

Researchers have revealed that it is possible for volunteers to re-associate one body part to another using virtual reality. This association is nonetheless likely to be weaker than a natural association.

The recent study contributes to the expanding perspectives on body schemes of augmented humans and understanding their limitations. Body-part re-association can be applied to developing functional prosthesis and embodied tools in the future.

Illusory body ownership can be induced by visuo-motor synchrony; It appears as if a virtual body is one’s own body if the virtual body moves synchronously with one’s movements. It is possible to have illusory body ownership to various bodies with different appearances, including a transparent body (Kondo, et al., Scientific Reports, 2018). However, in most studies, virtual body parts were associated with the corresponding actual body parts. For example, the virtual left arm was synchronously moved with the actual left arm.

The research team focused on the difference in correspondence between the actual and virtual body parts. In 2017, Sasaki, Inami et al. (SIGGRAPH 2017) created two additional robot arms by controlling them with left and right foot movements (‘MetaLimbs’). However, the sense of ownership of the robotic arms has not been investigated in detail. The team aimed to investigate whether the illusory body ownership can be induced by body-part re-association at different levels of the human body hierarchy: a virtual left arm and the actual right thumb.

Twenty participants moved the right thumb voluntarily when they observed a virtual left arm through a head-mounted display for 5 minutes. The virtual left arm was moved either synchronized or asynchronized with the right thumb. It was found that participants felt as if their right thumb had become the left arm and the virtual left arm was a part of their own body in the synchronous condition. However, the sense of ownership was not very strong, suggesting that the re-association of different body parts may be weaker than the natural association. This may be because the re-association was performed for only 5 minutes in the experiment. The study contributes to expanding perspectives on the human body or body scheme and offers the means to investigate the potentials and limitations of augmented humans. The body-part re-association may be applied to developing functional prosthesis and embodied tools in the future.

Trapecar M., Communal C., Velazquez J., Maass C.A., Huang Y.J., Schneider K., Wright C.W., Butty V., Eng G., Yilmaz O., Trumper D., Griffith L.G. in Cell Systems.

MIT biological engineers have created a multitissue model that lets them study the relationships between different organs and the immune system, on a specialized microfluidic platform seeded with human cells.

Using this type of model, sometimes called “organs-on-a-chip” or “physiome-on-a-chip,” the research team was able to explore the role of circulating immune cells in ulcerative colitis and other inflammatory diseases. They also discovered that a metabolic byproduct generated by bacteria living in the human gut plays an important role under these inflammatory conditions.

According to the abstract, although the association between the microbiome and IBD and liver diseases is known, the cause and effect remain elusive. By connecting human microphysiological systems of the gut, liver, and circulating Treg and Th17 cells, reserchers created a multi-organ model of ulcerative colitis (UC) ex vivo. The approach shows microbiome-derived short-chain fatty acids (SCFAs) to either improve or worsen UC severity, depending on the involvement of effector CD4 T cells. Using multiomics, they found SCFAs increased production of ketone bodies, glycolysis, and lipogenesis, while markedly reducing innate immune activation of the UC gut. However, during acute T cell-mediated inflammation, SCFAs exacerbated CD4+ T cell-effector function, partially through metabolic reprograming, leading to gut barrier disruption and hepatic injury. These paradoxical findings underscore the emerging utility of human physiomimetic technology in combination with systems immunology to study causality and the fundamental entanglement of immunity, metabolism, and tissue homeostasis.

Lucia L. Prieto-Godino, Ana F. Silbering, Mohammed A. Khallaf, Steeve Cruchet, Karolina Bojkowska, Sylvain Pradervand, Bill S. Hansson, Markus Knaden and Richard Benton in Science Advances

Preventing the death of neurons during brain growth means these ‘zombie’ cells can develop into functioning neurons, according to research in fruit flies from the Crick, the University of Lausanne (UNIL) and the Max Planck Institute for Chemical Ecology.

Programmed cell death (PCD) is widespread during neurodevelopment, eliminating the surpluses of neuronal production. Using the Drosophila olfactory system, the authors examined the potential of cells fated to die to contribute to circuit evolution. Inhibition of PCD is sufficient to generate new cells that express neural markers and exhibit odor-evoked activity. These “undead” neurons express a subset of olfactory receptors that is enriched for relatively recent receptor duplicates and includes some normally found in different chemosensory organs and life stages. Moreover, undead neuron axons integrate into the olfactory circuitry in the brain, forming novel receptor/glomerular couplings. Comparison of homologous olfactory lineages across drosophilids reveals natural examples of fate change from death to a functional neuron. Last, they provide evidence that PCD contributes to evolutionary differences in carbon dioxide–sensing circuit formation in Drosophila and mosquitoes. These results reveal the remarkable potential of alterations in PCD patterning to evolve new neural pathways.

Inhibition of developmental PCD results in increased neuron numbers in the antenna

(A) Schematic of the D. melanogaster third antennal segment highlighting different sensory structures. (B) Schematic of the lineage of an antennal disc SOP cell that gives rise to a sensillum containing two neurons (illustrated on the right). The expression of a subset of molecular markers is shown: Elav is expressed in only three of four neural precursors; one of these (Naa) and the Elav-negative cell (Nbb) are eliminated by PCD. © Simplified summary of the PCD pathway in D. melanogaster, highlighting the elements relevant for this study. Several intermediate steps between the proapoptotic proteins (Rpr, Grim, Hid, and Skl) and the executioner caspases are not shown. (D) Representative images of anti-Elav immunofluorescence in whole-mount antennae from control [Df(3L)H99/+; the wild-type chromosome here and in other genotypes was derived from a w1118 parent] and PCD-deficient [Df(3L)H99/Df(3L)XR38] animals. Scale bar, 10 μm. Right: Quantifications of antennal neuron numbers of the indicated genotypes, including an additional control genotype [Df(3L)XR38/+] (n = 14, 14, and 13, respectively). Mixed sexes were analyzed; in all other experiments, female flies were used, except where noted otherwise. ***P = 0.0007216 for the comparison to Df(3L)H99/+ and P = 0.0013224 for the comparison to Df(3L)XR38/+ (Wilcoxon rank sum test, corrected for multiple comparisons using a Bonferroni correction). In this and subsequent panels, individual data points are shown, overlaid with boxes indicating the median and first and third quartiles of the data; whiskers show the limits of the distribution. (E) Representative images of anti-Elav immunofluorescence in whole-mount antennae from control (peb-Gal4/+) and PCD-blocked [peb-Gal4/+;UAS-miR(rpr,hid,grim)/+] animals. Scale bar, 10 μm. Right: Quantifications of neuron numbers of these genotypes. ***P = 2.4 × 10−7 (t test) (n = 19 and 21; control and PCD-blocked, respectively). (F) Representative images of anti-Elav immunofluorescence in whole-mount antennae from control (peb-Gal4/+) and PCD-blocked (peb-Gal4/+;UAS-p35/+) animals. Scale bar, 10 μm. Right: Quantifications of neuron numbers of these genotypes. *P = 0.024 (t test) (n = 10 and 11; control and PCD-blocked, respectively).

by Olivia J. Scheideler, Chun Yang, Molly Kozminsky, Kira I. Mosher, Roberto Falcón-Banchs, Emma C. Ciminelli, Andrew W. Bremer, Sabrina A. Chern, David V. Schaffer, and Lydia L. Sohn in Science Advances

Researchers have created a new technique that can rapidly “print’ two-dimensional arrays of cells and proteins that mimic a variety of cellular environments in the body.

Elucidating how the spatial organization of extrinsic signals modulates cell behavior and drives biological processes remains largely unexplored because of challenges in controlling spatial patterning of multiple microenvironmental cues in vitro. The authors describe a high-throughput method that directs simultaneous assembly of multiple cell types and solid-phase ligands across length scales within minutes. Their method involves lithographically defining hierarchical patterns of unique DNA oligonucleotides to which complementary strands, attached to cells and ligands-of-interest, hybridize. Highlighting the method’s power, researchers investigated how the spatial presentation of self-renewal ligand fibroblast growth factor-2 (FGF-2) and differentiation signal ephrin-B2 instruct single adult neural stem cell (NSC) fate. They found that NSCs have a strong spatial bias toward FGF-2 and identified an unexpected subpopulation exhibiting high neuronal differentiation despite spatially occupying patterned FGF-2 regions. Overall, their broadly applicable, DNA-directed approach enables mechanistic insight into how tissues encode regulatory information through the spatial presentation of heterogeneous signals.

In the new technique, cells and proteins are attached to a substrate via a DNA “tether.” The researchers used the technique to pattern neural stem cells alongside important cellular signaling proteins to find out how these proteins influence the cells’ ultimate fates: whether they remain stem cells or differentiate into mature neurons.

by Onur Aydin, Austin P. Passaro, Mohamed Elhebeary, Gelson J. Pagan-Diaz, Anthony Fan, Sittinon Nuethong, Rashid Bashir, Steven L. Stice, and M. Taher A. Saif in APL Bioengineering.

Scientists have created a platform on which you can grow both a culture of neurons and artificial muscles

Neuronal control of skeletal muscle bioactuators represents a critical milestone toward the realization of future biohybrid machines that may generate complex motor patterns and autonomously navigate through their environment. Animals achieve these feats using neural networks that generate robust firing patterns and coordinate muscle activity through neuromuscular units. The authors designed a versatile 3D neuron-muscle co-culture platform to serve as a test-bed for neuromuscular bioactuators. They used the platform in conjunction with microelectrode array electrophysiology to study the roles of synergistic interactions in the co-development of neural networks and muscle tissues. Their platform design enables co-culture of a neuronal cluster with up to four target muscle actuators, as well as quantification of muscle contraction forces. Using engineered muscle tissue targets, researchers first demonstrated the formation of functional neuromuscular bioactuators. They then investigated possible roles of long-range interactions in neuronal outgrowth patterns and observed preferential outgrowth toward muscles compared to the acellular matrix or fibroblasts, indicating muscle-specific chemotactic cues acting on motor neurons. Next, they showed that co-cultured muscle strips exhibited significantly higher spontaneous contractility as well as improved sarcomere assembly compared to muscles cultured alone. Finally, they performed microelectrode array measurements on neuronal cultures, which revealed that muscle-conditioned medium enhances overall neural firing rates and the emergence of synchronous bursting patterns. Overall, the study illustrates the significance of neuron-muscle cross talk for the in vitro development of neuromuscular bioactuators.

Bidirectional cross talk in developing co-cultures. (a) Representative brightfield images and overall time course of the ratio of active vs quiescent muscle strips in (i) co-cultures and (ii) muscle-only cultures. (b) Spontaneous contraction forces in muscle-only and co-culture samples at days 3, 5, and 7. Values are spontaneous contraction force averaged over a 30 s recording per muscle strip at each day, and box plots represent the 25th, 50th, and 75th percentiles with whiskers representing 1.5×IQR, n = 27 muscle strips for co-culture, n = 20 muscle strips for muscle-only at each day, *p < 0.05, and **p < 0.005 (Mann Whitney U test). © Comparison of the percentage of cross-striated muscle fibers between muscle-only and co-culture groups. Bars represent mean ± SD, n = 6 muscle strips for each group, and **p < 0.005 (Mann Whitney U test). Confocal images at the right show sample muscle fibers with and without cross-striations. (d) MEA raster plots of representative samples from (i) control and (ii) CM groups at day 9. Black dashed lines represent the individual spikes, blue dashed lines represent the bursts, and pink boxes outline the synchronous bursts. (e) Time evolution of the MEA burst rate of neurons in control and muscle CM groups. Box plots represent the 25th, 50th, and 75th percentiles with whiskers representing 1.5×IQR, the values are average burst rates per electrode over 10 min recording from the entire well, n = 12 wells each for control and CM at each day, **p < 0.005, and ***p < 0.0005 (student’s t-test). (f) Conceptual illustration of bidirectional cross talk and its functional outcomes. Scale bars: (a) 500 μm and © 10 μm.

by María Carmen Martín-Buro, Maria Wimber, Richard N. Henson and Bernhard P. Staresina in Journal of Neuroscience

Memories for past experiences can range from vague recognition to full-blown recall of associated details. Electroencephalography has shown that recall signals unfold a few hundred milliseconds after simple recognition, but has only provided limited insights into the underlying brain networks. Functional magnetic resonance imaging (fMRI) has revealed a “core recollection network” (CRN) centered on posterior parietal and medial temporal lobe regions, but the temporal dynamics of these regions during retrieval remain largely unknown. Here we used Magnetoencephalography in a memory paradigm assessing correct rejection (CR) of lures, item recognition (IR) and associative recall (AR) in human participants of both sexes. The authors found that power decreases in the alpha frequency band (10–12 Hz) systematically track different mnemonic outcomes in both time and space: Over left posterior sensors, alpha power decreased in a stepwise fashion from 500 ms onward, first from CR to IR and then from IR to AR. When projecting alpha power into source space, the CRN known from fMRI studies emerged, including posterior parietal cortex (PPC) and hippocampus. While PPC showed a monotonic change across conditions, hippocampal effects were specific to recall. These region-specific effects were corroborated by a separate fMRI dataset. Importantly, alpha power time courses revealed a temporal dissociation between item and associative memory in hippocampus and PPC, with earlier AR effects in hippocampus. Researchers data thus link engagement of the CRN to the temporal dynamics of episodic memory and highlight the role of alpha rhythms in revealing when and where different types of memories are retrieved.

by Yu Toyoshima, Stephen Wu, Manami Kanamori, Hirofumi Sato, Moon Sun Jang, Suzu Oe, Yuko Murakami, Takayuki Teramoto, Chanhyun Park, Yuishi Iwasaki, Takeshi Ishihara, Ryo Yoshida & Yuichi Iino in BMC Biology

Researchers have designed a new computer program to identify each nerve cell in high-definition fluorescent microscope images of living worms

Annotation of cell identity is an essential process in neuroscience that allows comparison of cells, including that of neural activities across different animals. In Caenorhabditis elegans, although unique identities have been assigned to all neurons, the number of annotatable neurons in an intact animal has been limited due to the lack of quantitative information on the location and identity of neurons.

The authors present a dataset that facilitates the annotation of neuronal identities, and demonstrate its application in a comprehensive analysis of whole-brain imaging. They systematically identified neurons in the head region of 311 adult worms using 35 cell-specific promoters and created a dataset of the expression patterns and the positions of the neurons. Researchers found large positional variations that illustrated the difficulty of the annotation task. They investigated multiple combinations of cell-specific promoters driving distinct fluorescence and generated optimal strains for the annotation of most head neurons in an animal. The authors also developed an automatic annotation method with human interaction functionality that facilitates annotations needed for whole-brain imaging.

The brains of worms are not stationary inside skulls. Neurons (red) and other cells (blue) naturally shift position as an adult C. elegans eats or moves around in its environment. The head of this animal is on the right side of the video. Researchers were surprised to learn that neurons’ locations vary between individuals as well.

Our neuron ID dataset and optimal fluorescent strains enable the annotation of most neurons in the head region of adult C. elegans, both in full-automated fashion and a semi-automated version that includes human interaction functionalities. The method can potentially be applied to model species used in research other than C. elegans, where the number of available cell-type-specific promoters and their variety will be an important consideration.

by Abdulmalik Obaid, Mina-Elraheb Hanna, Yu-Wei Wu, Mihaly Kollo, Romeo Racz, Matthew R. Angle, Jan Müller, Nora Brackbill, William Wray, Felix Franke, E. J. Chichilnisky, Andreas Hierlemann, Jun B. Ding, Andreas T. Schaefer, and Nicholas A. Melosh in Science Advances

New brain-reading technology could help the development of brainwave-controlled devices

Multi-channel electrical recordings of neural activity in the brain is an increasingly powerful method revealing new aspects of neural communication, computation, and prosthetics. However, while planar silicon-based CMOS devices in conventional electronics scale rapidly, neural interface devices have not kept pace. The authors present a new strategy to interface silicon-based chips with three-dimensional microwire arrays, providing the link between rapidly-developing electronics and high density neural interfaces. The system consists of a bundle of microwires mated to large-scale microelectrode arrays, such as camera chips. This system has excellent recording performance, demonstrated via single unit and local-field potential recordings in isolated retina and in the motor cortex or striatum of awake moving mice. The modular design enables a variety of microwire types and sizes to be integrated with different types of pixel arrays, connecting the rapid progress of commercial multiplexing, digitisation and data acquisition hardware together with a three-dimensional neural interface.

In vivo recording in awake moving mice.

(A) A schematic of the in vivo recording setup. (B) Left: Illustration of recording across a large spatial extent with a microwire bundle in the motor cortex. Right: Representative traces of electrophysiological activity (300 to 6000 Hz) from 163 microwires (background traces). Highlighted traces from 67 wires show neural action potentials of a 50-ms snapshot of motor cortical activity during motion. The color code represents the relative positions of the microwires. © Representative traces showing detailed motor cortical activity from the 67 wires highlighted in (B). The shaded areas indicate the moving episodes of the mouse. Insets show a close look of the representative traces during moving (top) and nonmoving (bottom) states. (D) Raster plot of detected units after spike sorting in a motor cortical recording. Insets show two representative spike-averaged waveforms. Gray traces are 400 randomly selected raw waveforms of two representative detected spikes. (E) Significantly higher spiking rates were observed during running in both motor cortical and striatal recordings (motor cortex: ***P < 0.001 and striatum: **P < 0.01; 30 trials in both areas). (F) Representative traces (unfiltered) of striatal recording. Both fluctuation in LFP and neural spikes were observed. (G) Gamma band power was significantly larger during running compared with the quiescent state in the striatum (P < 0.01; 30 trials).

by Omer Ali Bayraktar, Theresa Bartels, Staffan Holmqvist, Vitalii Kleshchevnikov, Araks Martirosyan, Damon Polioudakis, Lucile Ben Haim, Adam M. H. Young, Mykhailo Y. Batiuk, Kirti Prakash, Alexander Brown, Kenny Roberts, Mercedes F. Paredes, Riki Kawaguchi, et al. in Nature Neuroscience

New research on brain structure highlights cells linked to Alzheimer’s and autism. Astrocytes organised into layers in similar way to neurons

Although the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells show distinct layering. In the present study, we developed a high-content pipeline, the large-area spatial transcriptomic (LaST) map, which can quantify single-cell gene expression in situ. Screening 46 candidate genes for astrocyte diversity across the mouse cortex, researchers identified superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons. Astrocyte layer features, established in the early postnatal cortex, mostly persisted in adult mouse and human cortex. Single-cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.

“This study shows that the cortical architecture is more complex than previously thought. It provides a basis to begin to understand the precise roles played by astrocytes, and how they are involved in human neurodevelopmental and neurodegenerative diseases.” Professor David Rowitch, Head of Paediatrics at the University of Cambridge

by Amanda M Brown, Joshua J White, Meike E van der Heijden, Joy Zhou, Tao Lin, Roy V Sillitoe in eLife

New insight on what happens in brain cells to cause tremors in mice has been published in eLife Sciences

Tremor is currently ranked as the most common movement disorder. The brain regions and neural signals that initiate the debilitating shakiness of different body parts remain unclear. The authors found that genetically silencing cerebellar Purkinje cell output blocked tremor in mice that were given the tremorgenic drug harmaline. They show in awake behaving mice that the onset of tremor is coincident with rhythmic Purkinje cell firing, which alters the activity of their target cerebellar nuclei cells. They mimic the tremorgenic action of the drug with optogenetics and present evidence that highly patterned Purkinje cell activity drives a powerful tremor in otherwise normal mice. Modulating the altered activity with deep brain stimulation directed to the Purkinje cell output in the cerebellar nuclei reduced tremor in freely moving mice. Together, the data implicate Purkinje cell connectivity as a neural substrate for tremor and a gateway for signals that mediate the disease.

by Shreyas M. Suryanarayana, Juan Pérez-Fernández, Brita Robertson & Sten Grillner in Nature Ecology & Evolution

Lamprey study reveals the early evolution of the cortex

Amniotes, such as mammals and reptiles, have vision and other senses represented in the pallium, whereas anamniotes, such as amphibians, fish and cyclostomes (including lampreys), which diverged much earlier, were historically thought to process olfactory information predominantly or even exclusively in the pallium. The authors show that there is a separate visual area with retinotopic representation, and that somatosensory information from the head and trunk is represented in an adjacent area in the lamprey pallial cortex (lateral pallium). These cortical sensory areas flank a non-primary-sensory motor area. Both vision and somatosensation are relayed via the thalamus. These findings suggest that the basic sensorimotor representation of the mammalian neocortex, as well as the sensory thalamocortical relay, had already evolved in the last common ancestor of cyclostomes and gnathostomes around 560 million years ago.

by Solène Neyret, Anna I. Bellido Rivas, Xavi Navarro and Mel Slater in Frontiers in Robotics and AI.

Researchers examined the difference between how we believe we look, and how we view our own body from an outsider’s perspective. What they found was that people rate their own body more negatively when embodied in it, compared to viewing their exact same body except as an outsider.

In this experiment, researchers aimed to measure the conscious internal representation of one’s body appearance and allow the participants to compare this to their ideal body appearance and to their real body appearance. They created a virtual representation of the internal image participants had of their own body shape. They also created a virtual body corresponding to the internal representation they had of their ideal body shape, and they built another virtual body based on their real body measures. Participants saw the three different virtual bodies from an embodied first-person perspective and from a third-person perspective and had to evaluate the appearance of those virtual bodies. Researchers observed that female participants evaluated their real body as more attractive when they saw it from a third-person perspective, and that their level of body dissatisfaction was lower after the experimental procedure. The authors believe that third-person perspective allowed female participants to perceive their real body shape without applying the negative prior beliefs usually associated to the “self”, and that this resulted in a more positive evaluation of their body shape. They speculate that this method could be applied with patients suffering from eating disorders, by making their body perception more realistic and therefore improve their body satisfaction.

Avatar seen in first-person perspective, on the left, front view of the avatar reflected in the mirror and yellow balls moving toward the legs to create visuo-tactile feedback. On the right, view of the virtual body when the participant looks down.

Avatar seen in third-person perspective, from the point of view of the participant.

by Kristin Weineck, Francisco García-Rosales, Julio C. Hechavarría in PLOS Biology

Oscillations in the fronto-striatal network predict whether a bat is about to use echolocation or vocalized communication

The ability to vocalize is ubiquitous in vertebrates, but neural networks underlying vocal control remain poorly understood. The authors performed simultaneous neuronal recordings in the frontal cortex and dorsal striatum (caudate nucleus, CN) during the production of echolocation pulses and communication calls in bats. This approach allowed them to assess the general aspects underlying vocal production in mammals and the unique evolutionary adaptations of bat echolocation. The data indicate that before vocalization, a distinctive change in high-gamma and beta oscillations (50–80 Hz and 12–30 Hz, respectively) takes place in the bat frontal cortex and dorsal striatum. Such precise fine-tuning of neural oscillations could allow animals to selectively activate motor programs required for the production of either echolocation or communication vocalizations. Moreover, the functional coupling between frontal and striatal areas, occurring in the theta oscillatory band (4–8 Hz), differs markedly at the millisecond level, depending on whether the animals are in a navigational mode (that is, emitting echolocation pulses) or in a social communication mode (emitting communication calls). Overall, this study indicates that fronto-striatal oscillations could provide a neural correlate for vocal control in bats.

by Nabil Imam & Thomas A. Cleland in Nature Machine Intelligence

The precise mechanics of how mammals learn and identify smells have long eluded scientists. New research explains some of these functions through a computer algorithm inspired by the mammalian olfactory system.

The authors present a neural algorithm for the rapid online learning and identification of odourant samples under noise, based on the architecture of the mammalian olfactory bulb and implemented on the Intel Loihi neuromorphic system. As with biological olfaction, the spike timing-based algorithm utilizes distributed, event-driven computations and rapid (one shot) online learning. Spike timing-dependent plasticity rules operate iteratively over sequential gamma-frequency packets to construct odour representations from the activity of chemosensor arrays mounted in a wind tunnel. Learned odourants then are reliably identified despite strong destructive interference. Noise resistance is further enhanced by neuromodulation and contextual priming. Lifelong learning capabilities are enabled by adult neurogenesis. The algorithm is applicable to any signal identification problem in which high-dimensional signals are embedded in unknown backgrounds.

by Jianglai Wu, Yajie Liang, Shuo Chen, Ching-Lung Hsu, Mariya Chavarha, Stephen W. Evans, Dongqing Shi, Michael Z. Lin, Kevin K. Tsia & Na Ji in Nature Methods

Combining two-photon fluorescent microscopy and all-optical laser scanning, researchers can image the brain of an alert mouse 1,000 times a second, recording the passage of millisecond electrical pulses through neurons.

Understanding information processing in the brain requires monitoring neuronal activity at high spatiotemporal resolution. Using an ultrafast two-photon fluorescence microscope empowered by all-optical laser scanning, the authors imaged neuronal activity in vivo at up to 3,000 frames per second and submicrometer spatial resolution. This imaging method enabled monitoring of both supra- and subthreshold electrical activity down to 345 μm below the brain surface in head-fixed awake mice.

Using a two-photon fluorescence microscope with an extra-large field of view, UC Berkeley researchers imaged neurons (green) in a large chunk of the cortex of the brain of a living mouse. The area shows neurites in a volume of 4.2 mm × 4.2 mm x 100 microns. The dark branches are blood vessels.

by Rongwen Lu, Yajie Liang, Guanghan Meng, Pengcheng Zhou, Karel Svoboda, Liam Paninski & Na Ji. in Nature Methods

Imaging neurons and neural circuits over large volumes at high speed and subcellular resolution is a difficult task. Incorporating a Bessel focus module into a two-photon fluorescence mesoscope, researchers achieved rapid volumetric imaging of neural activity over the mesoscale with synaptic resolution. They applied the technology to calcium imaging of entire dendritic spans of neurons as well as neural ensembles within multiple cortical regions over two hemispheres of the awake mouse brain.

When a neuron fires, calcium flows into the cell in a wave that sweeps along the cell body. Images of this infragranular neuron were obtained three times per second by two-dimensional scanning with a Bessel focus. Redder structures are deeper in the mouse cortex.

Waves of calcium flowing through neurons

Galvin V.C., Yang S.T., Paspalas C.D., Yang Y., Jin L.E., Datta D., Morozov Y.M., Lightbourne T.C., Lowet A.S., Rakic P., Arnsten A.F., Wang M. in Neuron.

Neuroscientists have uncovered a molecule that is key in helping neurons maintain information in working memory, which could lead to potential treatments for neurocognitive disorders.

Working memory relies on the dorsolateral prefrontal cortex (dlPFC), where microcircuits of pyramidal neurons enable persistent firing in the absence of sensory input, maintaining information through recurrent excitation. This activity relies on acetylcholine, although the molecular mechanisms for this dependence are not thoroughly understood. This study investigated the role of muscarinic M1 receptors (M1Rs) in the dlPFC using iontophoresis coupled with single-unit recordings from aging monkeys with naturally occurring cholinergic depletion. The authors found that M1R stimulation produced an inverted-U dose response on cell firing and behavioral performance when given systemically to aged monkeys. Immunoelectron microscopy localized KCNQ isoforms (Kv7.2, Kv7.3, and Kv7.5) on layer III dendrites and spines, similar to M1Rs. Iontophoretic manipulation of KCNQ channels altered cell firing and reversed the effects of M1R compounds, suggesting that KCNQ channels are one mechanism for M1R actions in the dlPFC. These results indicate that M1Rs may be an appropriate target to treat cognitive disorders with cholinergic alterations.

by Reuben Rideaux and Andrew E. Welchman in Journal of Neuroscience

Seeing movement promotes survival. It results from an uncertain interplay between evolution and experience, making it hard to isolate the drivers of computational architectures found in brains. The authors seek insight into motion perception using a neural network (MotionNet) trained on moving images to classify velocity. The network recapitulates key properties of motion direction and speed processing in biological brains, and they use it to derive, and test, understanding of motion (mis)perception at the computational, neural, and perceptual levels. Researchers show that diverse motion characteristics are largely explained by the statistical structure of natural images, rather than motion per se. First, they show how neural and perceptual biases for particular motion directions can result from the orientation structure of natural images. Second, they demonstrate an interrelation between speed and direction preferences in (macaque) MT neurons that can be explained by image autocorrelation. Third, they show that natural image statistics mean that speed and image contrast are related quantities. Finally, using behavioral tests (humans, both sexes), the authors show that it is knowledge of the speed-contrast association that accounts for motion illusions, rather than the distribution of movements in the environment (the “slow world” prior) as premised by Bayesian accounts. Together, this provides an exposition of motion speed and direction estimation, and produces concrete predictions for future neurophysiological experiments. More broadly, they demonstrate the conceptual value of marrying artificial systems with biological characterization, moving beyond “black box” reproduction of an architecture to advance understanding of complex systems, such as the brain.

Motion models and psychophysical tests of MotionNet predictions. a, Illustration comparing speed estimation by MotionNet versus a “slow world” prior model. Left, MotionNet represents speed as a distribution of activity (rV1), which is summed with a constant offset (es) to produce the final estimate (rMT). The Bayesian model takes the product of the likelihood and prior distributions. Right, Uncertainty can be manipulated by reducing image contrast or introducing variability in speed. For contrast, uncertainty is increased while signal amplitude is reduced, so MotionNet and the Bayesian model make equivalent predictions. For speed variability, uncertainty is increased while signal amplitude remains unchanged, and MotionNet and the Bayesian model make divergent predictions. b, Left, Illustrations of test stimuli, and their speed profiles, used in the psychophysical experiment. Right, Simulations showing the predictions made by the two models. c, Results of a representative human observer. d, e, Summary results of all observers for (d) speed bias and (e) estimate uncertainty. Separate repeated-measures ANOVA tests revealed main effects of condition for both speed bias (F(2,14) = 14.37, p = 0.005) and uncertainty (χ2(2,14) = 12.25, p = 0.002). Colors represent data from conditions shown in b (left). d, e, Dots indicate individual datum. Colors represent corresponding observers. Error bars indicate SEM. **p < 0.01, ***p < 0.001.

by Zirui Huang, Jun Zhang, Jinsong Wu, George A. Mashour, and Anthony G. Hudetz in Science Advances

Imaging reveals how cyclical patterns of brain activity differ between conscious and unresponsive individuals

The ongoing stream of human consciousness relies on two distinct cortical systems, the default mode network and the dorsal attention network, which alternate their activity in an anticorrelated manner. The authors examined how the two systems are regulated in the conscious brain and how they are disrupted when consciousness is diminished. They provide evidence for a “temporal circuit” characterized by a set of trajectories along which dynamic brain activity occurs. They demonstrate that the transitions between default mode and dorsal attention networks are embedded in this temporal circuit, in which a balanced reciprocal accessibility of brain states is characteristic of consciousness. Conversely, isolation of the default mode and dorsal attention networks from the temporal circuit is associated with unresponsiveness of diverse etiologies. These findings advance the foundational understanding of the functional role of anticorrelated systems in consciousness.

Stimulus modulations of CAPs and control analysis in psychiatric patients.

(A) Stimulus-induced CAP occurrence rate changes (against stimulus onset, t = 0) in baseline conscious condition, light sedation, and general anesthesia (n = 15). Student’s t tests (against zero) for the CAP occurrence rate changes were performed during the peak period of stimulus-evoked fMRI signal activity (4 to 6 s). Asterisks indicate significance at α < 0.05 after FDR correction. (B) Stimulus-induced CAP occurrence rate changes in healthy controls (n = 12), patients with MCS (n = 4), and patients with UWS (n = 6). © Spatial similarity of the eight CAPs between the main cohort and psychiatric cohort data. (D) Comparisons of the CAP occurrence rates for healthy control participants (CONTROL) versus schizophrenic (SCHZ), bipolar disorder (BIPOLAR), and attention deficit/hyperactive disorder (ADHD) patients by Student’s t tests. Red solid lines indicate significant group differences at α < 0.05 after FDR correction, and red dash lines indicate uncorrected significance at P < 0.05. Error bars indicate ±SD.

by Woong Bin Kim & Jun-Hyeong Cho in Nature Communications

A new study suggests that the formation of fear memory involves the strengthening of neural pathways between two brain areas: the hippocampus and the amygdala

In contextual fear conditioning, experimental subjects learn to associate a neutral context with an aversive stimulus and display fear responses to a context that predicts danger. Although the hippocampal–amygdala pathway has been implicated in the retrieval of contextual fear memory, the mechanism by which fear memory is encoded in this circuit has not been investigated. The authors show that activity in the ventral CA1 (vCA1) hippocampal projections to the basal amygdala (BA), paired with aversive stimuli, contributes to encoding conditioned fear memory. Contextual fear conditioning induced selective strengthening of a subset of vCA1–BA synapses, which was prevented under anisomycin-induced retrograde amnesia. Moreover, a subpopulation of BA neurons receives stronger monosynaptic inputs from context-responding vCA1 neurons, whose activity was required for contextual fear learning and synaptic potentiation in the vCA1–BA pathway. The study suggests that synaptic strengthening of vCA1 inputs conveying contextual information to a subset of BA neurons contributes to encoding adaptive fear memory for the threat-predictive context.

a Experimental setup for b. b Images showing eYFP expression in the vCA1 (left, green) and eYFP-labeled vCA1 axons in the amygdala (middle and right). Red, Nissl stain. LA, BLA, BMA, and CeA: lateral, basolateral, basomedial, and central nuclei of the amygdala, respectively. c Experimental setup for d. Top: vCA1 neurons projecting to the BA (vCA1: BA projectors) were retrogradely labeled with HSV-mCherry. Bottom: mice in FC group were fear conditioned in Context A as in Supplementary Fig. 1a. Mice in CTX group were exposed to Context A without a US. After 24 h, they were tested for freezing behavior in Context A. Brain tissues were then fixed 90 min later for c-Fos immunohistochemistry. Mice in HC group were left in their home cages until brain fixation. d Left: image showing vCA1: BA projectors (red) in the dorsal (dCA1), intermediate (iCA1), ventral CA1 hippocampus (vCA1), and ventral subiculum (vSub). vDG, ventral dentate gyrus. LEC, lateral entorhinal cortex. Middle: image showing c-Fos+ cells (green) and vCA1: BA projectors (mCherry+, red). A square indicates a c-Fos+ vCA1: BA projector. Right: quantification of c-Fos+ proportion among vCA1: BA projectors (6 mice per group). **p = 0.001, ***p < 0.001 (one-way ANOVA with post hoc comparisons). e Experimental setup for f–h. vCA1: BA projectors expressed hM4Di-mCherry or mCherry. We bilaterally injected retrograde CAV2-Cre into the BA and AAV-DIO-hM4Di-mCherry (hM4Di group) or AAV-DIO-mCherry (mCherry group) into the vCA1. f Images showing hM4Di-mCherry expression in vCA1: BA projectors (left and middle). Note no hM4Di-mCherry expression in the amygdala (right). g Behavioral training and testing protocols for h. h Quantification of freezing behavior on test days in the hM4Di (left, 10 mice) and mCherry groups (right, 8 mice) on test days. *p < 0.05, **p < 0.01 (two-way ANOVA with post hoc comparisons; group × treatment interaction, p < 0.05). Error bars indicate standard error of the mean (SEM).

by Margarita Khariton, Xian Kong, Jian Qin & Bo Wang in Nature Physics

Using advanced microscopy and mathematical modeling, researchers have discovered a pattern that governs the growth of neurons

Jamming models developed in inanimate matter have been widely used to describe cell packing in tissues, but predominantly neglect cell diversity, despite its prevalence in biology. Most tissues, animal brains in particular, comprise a mix of many cell types, with mounting evidence suggesting that neurons can recognize their respective types as they organize in space. How cell diversity revises the current jamming paradigm is unknown. Here, in the brain of the flatworm planarian Schmidtea mediterranea, which exhibits remarkable tissue plasticity within a simple, quantifiable nervous system, researchers identify a distinct packing state, ‘chromatic’ jamming. Combining experiments with computational modelling, they show that neurons of distinct types form independent percolating networks barring any physical contact. This jammed state emerges as cell packing configurations become constrained by cell type-specific interactions and therefore may extend to describe cell packing in similarly complex tissues composed of multiple cell types.

We think we’re learning more about the brain, but are we just replacing one story with another?

The selfish gene. The Big Bang. The greenhouse effect. Metaphors are at the heart of scientific thinking. They provide the means for both scientists and non-scientists to understand, think through and talk about abstract ideas in terms of more familiar objects or phenomena.

But if metaphors can illuminate, they can also constrain. In his new book, The Idea of the Brain, zoologist and historian Matthew Cobb tells the story of how scientists and philosophers have tried to understand the brain and how it works. In every age, Cobb shows, people have thought about the brain largely in terms of metaphors, drawn usually from the most exciting technology of the day, whether clocks or telephone exchanges or the contemporary obsession with computers. The brain, Cobb observes, “is more like a computer than like a clock”, but “even the simplest animal brain is not a computer like anything we have built, nor one we can yet envisage”.