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Abstract Inspired by the movement of bacteria and other microorganisms, researchers have developed artificial helical micro‐ and nanorobots that can perform corkscrew locomotion or helical path swimming under external energy actuation. In this paper, for the first time the locomotion of nonhelical multifunctional nanorobots that can swim in helical klinotactic trajectories, similarly to rod‐shaped bacteria, under rotating magnetic fields is investigated. These nanorobots consist of a rigid ferromagnetic nickel head connected to a rhodium tail by a flexible hydrogel‐based hollow hinge composed of chemically responsive chitosan and alginate multilayers. This design allows nanoswimmers switching between different dynamic behaviors—from in‐plane tumbling to helical klinotactic swimming—by varying the rotating magnetic field frequency and strength. It also adds a rich spectrum of swimming capabilities that can be adjusted by varying the type of applied magnetic fields and/or frequencies. A theoretical model is developed to analyze the propulsion mechanisms and predict the swimming behavior at distinct rotating magnetic frequencies. The model shows good agreement with the experimental results. Additionally, the biomedical capabilities of the nanoswimmers as drug delivery platforms are demonstrated. Unlike previous designs constitute metallic segments, the proposed nanoswimmers can encapsulate drugs into their hollow hinge and successfully release them to cells.

Rehabilitative robotics is an area in the medical field, where one can see a variety of different robotic applications, one of which is the use of robotic exoskeleton in rehabilitation of paraplegics. Current developments are only able to support paraplegics at most and require manual operation of crutches by the patient. In order to overcome this limitation, a theoretical model of a robotic device with actuated robotic crutches is proposed, which can be used to support people with high-level disability, such as quadriplegics who cannot use the existing solutions to perform walking gaits. This work presents kinematic trajectory planning of the proposed model and dynamic analysis of main movement stages. Finally, we present an open-loop control scheme that uses time scaling in order to track the desired joint trajectory of the under-actuated motion stage of crutch swinging. A simulated robotic model has also been developed using Simulink [version R2012b to R2014a]/SimMechanics ([version first generation] developed by Mathworks inc.) environment and has been used for verifying dynamic computations and simulating the robotic device movement under the open-loop control commands of joint torques.

Micron-scale swimmers move in the realm of negligible inertia, dominated by viscous drag forces. In this paper, we formulate the leading-order dynamics of a slender multi-link ( N -link) microswimmer assuming small-amplitude undulations about its straight configuration. The energy-optimal stroke to achieve a given prescribed displacement in a given time period is obtained as the largest eigenvalue solution of a constrained optimal control problem. Remarkably, the optimal stroke is an ellipse lying within a two-dimensional plane in the ( N – 1)-dimensional space of joint angles, where N can be arbitrarily large. For large N , the optimal stroke is a traveling wave of bending, modulo edge effects. If the number of shape variables is small, we can consider the same problem when the prescribed displacement in one time period is large, and not attainable with small variations of the joint angles. The fully nonlinear optimal control problem is solved numerically for the cases N = 3 (Purcell’s three-link swimmer) and N = 5 showing that, as the prescribed displacement becomes small, the optimal solutions obtained using the small-amplitude assumption are recovered. We also show that, when the prescribed displacements become large, the picture is different. For N = 3 we recover the non-convex planar loops already known from previous studies. For N = 5 we obtain non-planar loops, raising the question of characterizing the geometry of complex high-dimensional loops.

The classical model of spring-loaded inverted pendulum (SLIP) and its extensions have been widely accepted as a simple description of dynamic legged locomotion at various scales in humans, legged robots and animals. Similar to the majority of models in the literature, the SLIP model assumes ideal sticking contact of the foot. However, there are practical scenarios of low ground friction that causes foot slippage, which can have a significant influence on dynamic behaviour. In this work, an extension of the SLIP model with two masses and torque actuation is considered, which accounts for possible slippage under Coulomb's friction law. The hybrid dynamics of this model is formulated and numerical simulations under representative parameter values reveal several types of stable periodic solutions with stick-slip transitions. Remarkably, it is found that slippage due to low friction can sometimes increase average speed and improve energetic efficiency by significantly reducing the mechanical cost of transport.

People can use their sense of hearing for discerning thermal properties, though they are for the most part unaware that they can do so. While people unequivocally claim that they cannot perceive the temperature of pouring water through the auditory properties of hearing it being poured, our research further strengthens the understanding that they can. This multimodal ability is implicitly acquired in humans, likely through perceptual learning over the lifetime of exposure to the differences in the physical attributes of pouring water. In this study, we explore people's perception of this intriguing cross modal correspondence, and investigate the psychophysical foundations of this complex ecological mapping by employing machine learning. Our results show that not only can the auditory properties of pouring water be classified by humans in practice, the physical characteristics underlying this phenomenon can also be classified by a pre-trained deep neural network., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wenger, Maimon, Yizhar, Snir, Sasson and Amedi.)

Rodents continuously move their heads and whiskers in a coordinated manner while perceiving objects through whisker-touch. Studies in head-fixed rodents showed that the ventroposterior medial (VPM) and posterior medial (POm) thalamic nuclei code for whisker kinematics, with POm involvement reduced in awake animals. To examine VPM and POm involvement in coding head and whisker kinematics in awake, head-free conditions, we recorded thalamic neuronal activity and tracked head and whisker movements in male mice exploring an open arena. Using optogenetic tagging, we found that in freely moving mice, both nuclei equally coded whisker kinematics and robustly coded head kinematics. The fraction of neurons coding head kinematics increased after whisker trimming, ruling out whisker-mediated coding. Optogenetic activation of thalamic neurons evoked overt kinematic changes and increased the fraction of neurons leading changes in head kinematics. Our data suggest that VPM and POm integrate head and whisker information and can influence head kinematics during tactile perception., (© 2024. The Author(s).)

Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein-coupled receptor pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumerilii ciliary opsin (PdCO) is an efficient, versatile, light-activated bistable G-protein-coupled receptor that can suppress synaptic transmission in mammalian neurons with high temporal precision in vivo. PdCO has useful biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping., (© 2024. The Author(s).)

Although aggression is associated with several psychiatric disorders, there is no effective treatment nor a rigorous definition for "pathological aggression". Mice make a valuable model for studying aggression. They have a dynamic social structure that depends on the habitat and includes reciprocal interactions between the mice's aggression levels, social dominance hierarchy (SDH), and resource allocation. Nevertheless, the classical behavioral tests for territorial aggression and SDH in mice are reductive and have limited ethological and translational relevance. Recent work has explored the use of semi-natural environments to simultaneously study dominance-related behaviors, resource allocation, and aggressive behavior. Semi-natural setups allow experimental control of the environment combined with manipulations of neural activity. We argue that these setups can help bridge the translational gap in aggression research toward discovering neuronal mechanisms underlying maladaptive aggression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess axon collaterals within the globus pallidus (GPe) (bridging collaterals), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches in mice to dissect the roles of dSPN GPe collaterals in motor function. We find that dSPNs projecting to the SNr send synchronous motor-related information to the GPe via axon collaterals. Inhibition of native activity in dSPN GPe terminals impairs motor activity and function via regulation of Npas1 neurons. We propose a model by which dSPN GPe axon collaterals (striatopallidal Go pathway) act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 neurons., (© 2023. Springer Nature Limited.)

Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent release of glucocorticoid hormones is a key response that mobilizes fuel stores to meet energy demands 1-5 . Despite the importance of the HPA axis response, the neural mechanisms that drive its activation during energy deficit are unknown. Here, we show that fasting-activated hypothalamic agouti-related peptide (AgRP)-expressing neurons trigger and are essential for fasting-induced HPA axis activation. AgRP neurons do so through projections to the paraventricular hypothalamus (PVH), where, in a mechanism not previously described for AgRP neurons, they presynaptically inhibit the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis (BNST) that otherwise restrain activity of corticotrophin-releasing hormone (CRH)-expressing neurons. This disinhibition of PVH Crh neurons requires γ-aminobutyric acid (GABA)/GABA-B receptor signalling and potently activates the HPA axis. Notably, stimulation of the HPA axis by AgRP neurons is independent of their induction of hunger, showing that these canonical 'hunger neurons' drive many distinctly different adaptations to the fasted state. Together, our findings identify the neural basis for fasting-induced HPA axis activation and uncover a unique means by which AgRP neurons activate downstream neurons: through presynaptic inhibition of GABAergic afferents. Given the potency of this disinhibition of tonically active BNST afferents, other activators of the HPA axis, such as psychological stress, may also work by reducing BNST inhibitory tone onto PVH Crh neurons., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The medial prefrontal cortex (mPFC) mediates a variety of complex cognitive functions via its vast and diverse connections with cortical and subcortical structures. Understanding the patterns of synaptic connectivity that comprise the mPFC local network is crucial for deciphering how this circuit processes information and relays it to downstream structures. To elucidate the synaptic organization of the mPFC, we developed a high-throughput optogenetic method for mapping large-scale functional synaptic connectivity in acute brain slices. We show that in male mice, mPFC neurons that project to the basolateral amygdala (BLA) display unique spatial patterns of local-circuit synaptic connectivity, which distinguish them from the general mPFC cell population. When considering synaptic connections between pairs of mPFC neurons, the intrinsic properties of the postsynaptic cell and the anatomical positions of both cells jointly account for ~7.5% of the variation in the probability of connection. Moreover, anatomical distance and laminar position explain most of this fraction in variation. Our findings reveal the factors determining connectivity in the mPFC and delineate the architecture of synaptic connections in the BLA-projecting subnetwork., (© 2023. The Author(s).)

Focal cortical epilepsies are frequently refractory to available anticonvulsant drug therapies. One key factor contributing to this state is the limited availability of animal models that allow to reliably study focal cortical seizures and how they recruit surrounding brain areas in vivo. In this study, we selectively expressed the inhibitory chemogenetic receptor, hM4D, in GABAergic neurons in focal cortical areas using viral gene transfer. GABAergic silencing using Clozapine-N-Oxide (CNO) demonstrated reliable induction of local epileptiform events in the electroencephalogram signal of awake freely moving mice. Anesthetized mice experiments showed consistent induction of focal epileptiform-events in both the barrel cortex (BC) and the medial prefrontal cortex (mPFC), accompanied by high-frequency oscillations, a known characteristic of human seizures. Epileptiform-events showed propagation indication with favored propagation pathways: from the BC on 1 hemisphere to its counterpart and from the BC to the mPFC, but not vice-versa. Lastly, sensory whisker-pad stimulation evoked BC epileptiform events post-CNO, highlighting the potential use of this model in studying sensory-evoked seizures. Combined, our results show that targeted chemogenetic inhibition of GABAergic neurons using hM4D can serve as a novel, versatile, and reliable model of focal cortical epileptic activity suitable for systematically studying cortical ictogenesis in different cortical areas., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Extrastriate Body Area (EBA) participates in the visual perception and motor actions of body parts. We recently showed that EBA's perceptual function develops independently of visual experience, responding to stimuli with body-part information in a supramodal fashion. However, it is still unclear if the EBA similarly maintains its action-related function. Here, we used fMRI to study motor-evoked responses and connectivity patterns in the congenitally blind brain. We found that, unlike the case of perception, EBA does not develop an action-related response without visual experience. In addition, we show that congenital blindness alters EBA's connectivity profile in a counterintuitive way-functional connectivity with sensorimotor cortices dramatically decreases, whereas connectivity with perception-related visual occipital cortices remains high. To the best of our knowledge, we show for the first time that action-related functions and connectivity in the visual cortex could be contingent on visuomotor experience. We further discuss the role of the EBA within the context of visuomotor control and predictive coding theory., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yizhar, Tal and Amedi.)

Current advancements in both technology and science allow us to manipulate our sensory modalities in new and unexpected ways. In the present study, we explore the potential of expanding what we perceive through our natural senses by utilizing a visual-to-auditory sensory substitution device (SSD), the EyeMusic, an algorithm that converts images to sound. The EyeMusic was initially developed to allow blind individuals to create a spatial representation of information arriving from a video feed at a slow sampling rate. In this study, we aimed to use the EyeMusic for the blind areas of sighted individuals. We use it in this initial proof-of-concept study to test the ability of sighted subjects to combine visual information with surrounding auditory sonification representing visual information. Participants in this study were tasked with recognizing and adequately placing the stimuli, using sound to represent the areas outside the standard human visual field. As such, the participants were asked to report shapes' identities as well as their spatial orientation (front/right/back/left), requiring combined visual (90° frontal) and auditory input (the remaining 270°) for the successful performance of the task (content in both vision and audition was presented in a sweeping clockwise motion around the participant). We found that participants were successful at a highly above chance level after a brief 1-h-long session of online training and one on-site training session of an average of 20 min. They could even draw a 2D representation of this image in some cases. Participants could also generalize, recognizing new shapes they were not explicitly trained on. Our findings provide an initial proof of concept indicating that sensory augmentation devices and techniques can potentially be used in combination with natural sensory information in order to expand the natural fields of sensory perception., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shvadron, Snir, Maimon, Yizhar, Harel, Poradosu and Amedi.)

Physical exercise is known to augment brain functioning, improving memory and cognition. However, while some of the physiological effects of physical activity on the brain are known, little is known about its effects on the neural code. Using calcium imaging in freely behaving mice, we study how voluntary exercise affects the quality and long-term stability of hippocampal place codes. We find that running accelerates the emergence of a more informative spatial code in novel environments and increases code stability over days and weeks. Paradoxically, although runners demonstrated an overall more stable place code than their sedentary peers, their place code changed faster when controlling for code quality level. A model-based simulation shows that the combination of improved code quality and faster representational drift in runners, but neither of these effects alone, could account for our results. Thus, exercise may enhance hippocampal function via a more informative and dynamic place code., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Greater cortical gyrification (GY) is linked with enhanced cognitive abilities and is also negatively related to cortical thickness (CT). Individuals who are congenitally blind (CB) exhibits remarkable functional brain plasticity which enables them to perform certain non-visual and cognitive tasks with supranormal abilities. For instance, extensive training using touch and audition enables CB people to develop impressive skills and there is evidence linking these skills to cross-modal activations of primary visual areas. There is a cascade of anatomical, morphometric and functional-connectivity changes in non-visual structures, volumetric reductions in several components of the visual system, and CT is also increased in CB. No study to date has explored GY changes in this population, and no study has explored how variations in CT are related to GY changes in CB. T1-weighted 3D structural magnetic resonance imaging scans were acquired to examine the effects of congenital visual deprivation in cortical structures in a healthy sample of 11 CB individuals (6 male) and 16 age-matched sighted controls (SC) (10 male). In this report, we show for the first time an increase in GY in several brain areas of CB individuals compared to SC, and a negative relationship between GY and CT in the CB brain in several different cortical areas. We discuss the implications of our findings and the contributions of developmental factors and synaptogenesis to the relationship between CT and GY in CB individuals compared to SC. F., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arend, Yuen, Yizhar, Chebat and Amedi.)

The phenomenology of the blind has provided an age-old, unparalleled means of exploring the enigmatic link between the brain and mind. This paper delves into the unique phenomenological experience of a man who became blind in adulthood. He subsequently underwent both an Argus II retinal prosthesis implant and training, and extensive training on the EyeMusic visual to auditory sensory substitution device (SSD), thereby becoming the first reported case to date of dual proficiency with both devices. He offers a firsthand account into what he considers the great potential of combining sensory substitution devices with visual prostheses as part of a complete visual restoration protocol. While the Argus II retinal prosthesis alone provided him with immediate visual percepts by way of electrically stimulated phosphenes elicited by the device, the EyeMusic SSD requires extensive training from the onset. Yet following the extensive training program with the EyeMusic sensory substitution device, our subject reports that the sensory substitution device allowed him to experience a richer, more complex perceptual experience, that felt more "second nature" to him, while the Argus II prosthesis (which also requires training) did not allow him to achieve the same levels of automaticity and transparency. Following long-term use of the EyeMusic SSD, our subject reported that visual percepts representing mainly, but not limited to, colors portrayed by the EyeMusic SSD are elicited in association with auditory stimuli, indicating the acquisition of a high level of automaticity. Finally, the case study indicates an additive benefit to the combination of both devices on the user's subjective phenomenological visual experience., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Optogenetic actuators enable highly precise spatiotemporal interrogation of biological processes at levels ranging from the subcellular to cells, circuits and behaving organisms. Although their application in neuroscience has traditionally focused on the control of spiking activity at the somatodendritic level, the scope of optogenetic modulators for direct manipulation of presynaptic functions is growing. Presynaptically localized opsins combined with light stimulation at the terminals allow light-mediated neurotransmitter release, presynaptic inhibition, induction of synaptic plasticity and specific manipulation of individual components of the presynaptic machinery. Here, we describe presynaptic applications of optogenetic tools in the context of the unique cell biology of axonal terminals, discuss their potential shortcomings and outline future directions for this rapidly developing research area., (© 2022. Springer Nature America, Inc.)

Many organisms sense light using rhodopsins, photoreceptive proteins containing a retinal chromophore. Here we report the discovery, structure and biophysical characterization of bestrhodopsins, a microbial rhodopsin subfamily from marine unicellular algae, in which one rhodopsin domain of eight transmembrane helices or, more often, two such domains in tandem, are C-terminally fused to a bestrophin channel. Cryo-EM analysis of a rhodopsin-rhodopsin-bestrophin fusion revealed that it forms a pentameric megacomplex (~700 kDa) with five rhodopsin pseudodimers surrounding the channel in the center. Bestrhodopsins are metastable and undergo photoconversion between red- and green-absorbing or green- and UVA-absorbing forms in the different variants. The retinal chromophore, in a unique binding pocket, photoisomerizes from all-trans to 11-cis form. Heterologously expressed bestrhodopsin behaves as a light-modulated anion channel., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

There is no question that genetically encoded tools have revolutionized neuroscience. These include optically modulated tools for writing-in (optogenetics) and reading-out (calcium, voltage, and neurotransmitter indicators) neural activity as well as precision expression of these reagents using virally mediated delivery. With few exceptions, these powerful approaches are derived from naturally occurring molecules that are sourced from diverse organisms that span all kingdoms of life. Successful expression of genetic tools in standard neuroscience model organisms requires optimizing gene structure, taking into account differences in both protein translation and trafficking. Myriad approaches have resolved these two challenges, resulting in order-of-magnitude increases in functional expression. In this chapter, we focus on synthesizing prior experience in successfully enabling the transition of genes across kingdoms with a goal of facilitating the production of the next generation of molecular tools for neuroscience. We then provide a detailed protocol that allows expression and testing of novel genetically encoded tools in mammalian cell lines and primary cultured neurons., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Optogenetic techniques have been developed to allow control over the activity of selected cells within a highly heterogeneous tissue, using a combination of genetic engineering and light. Optogenetics employs natural and engineered photoreceptors, mostly of microbial origin, to be genetically introduced into the cells of interest. As a result, cells that are naturally light-insensitive can be made photosensitive and addressable by illumination and precisely controllable in time and space. The selectivity of expression and subcellular targeting in the host is enabled by applying control elements such as promoters, enhancers and specific targeting sequences to the employed photoreceptor-encoding DNA. This powerful approach allows precise characterization and manipulation of cellular functions and has motivated the development of advanced optical methods for patterned photostimulation. Optogenetics has revolutionized neuroscience during the past 15 years and is primed to have a similar impact in other fields, including cardiology, cell biology and plant sciences. In this Primer, we describe the principles of optogenetics, review the most commonly used optogenetic tools, illumination approaches and scientific applications and discuss the possibilities and limitations associated with optogenetic manipulations across a wide variety of optical techniques, cells, circuits and organisms., Competing Interests: Competing interests Z.-H.P. is a co-inventor on patents related to optogenetic vision restoration and is also a co-founder and scientific advisor of Ray Therapeutics. The other authors declare no competing interests.

Neurophotonics was launched in 2014 coinciding with the launch of the BRAIN Initiative focused on development of technologies for advancement of neuroscience. For the last seven years, Neurophotonics ' agenda has been well aligned with this focus on neurotechnologies featuring new optical methods and tools applicable to brain studies. While the BRAIN Initiative 2.0 is pivoting towards applications of these novel tools in the quest to understand the brain, this status report reviews an extensive and diverse toolkit of novel methods to explore brain function that have emerged from the BRAIN Initiative and related large-scale efforts for measurement and manipulation of brain structure and function. Here, we focus on neurophotonic tools mostly applicable to animal studies. A companion report, scheduled to appear later this year, will cover diffuse optical imaging methods applicable to noninvasive human studies. For each domain, we outline the current state-of-the-art of the respective technologies, identify the areas where innovation is needed, and provide an outlook for the future directions., (© 2022 The Authors.)

Manipulating sensory and motor cues can cause an illusionary perception of ownership of a fake body part. Presumably, the illusion can work as long as the false body part's position and appearance are anatomically plausible. Here, we introduce an illusion that challenges past assumptions on body ownership. We used virtual reality to switch and mirror participants' views of their hands. When a participant moves their physical hand, they see the incongruent virtual hand moving. The result is an anatomically implausible configuration of the fake hand. Despite the hand switch, participants reported significant body ownership sensations over the virtual hands. In the first between-group experiment, we found that the strength of body ownership over the incongruent hands was similar to that of congruent hands. Whereas, in the second within-group experiment, anatomical incongruency significantly decreased body ownership. Still, participants reported significant body ownership sensations of the switched hands. Curiously, we found that perceived levels of agency mediate the effect of anatomical congruency on body ownership. These findings offer a fresh perspective on the relationship between anatomical plausibility and assumed body ownership. We propose that goal-directed and purposeful actions can override anatomical plausibility constraints and discuss this in the context of the immersive properties of virtual reality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yizhar, Giron, Wenger, Chetrit, Ostrin, Friedman and Amedi.)

Mammalian social interactions are orchestrated by a wide array of neural circuits. While some aspects of social behaviors are driven by subcortical circuits, and are considered to be highly conserved and hard-wired, others require dynamic and context-dependent modulation that integrates current state, past experience and goal-driven action selection. These cognitive social processes are known to be dependent on the integrity of the prefrontal cortex. However, the circuit mechanisms through which the prefrontal cortex supports complex social functions are still largely unknown, and it is unclear if and how they diverge from prefrontal control of behavior outside of the social domain. Here we review recent studies exploring the role of prefrontal circuits in mammalian social functions, and attempt to synthesize these findings to a holistic view of prefrontal control of sociability., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

All-optical methods for imaging and manipulating brain networks with high spatial resolution are fundamental to study how neuronal ensembles drive behavior. Stimulation of neuronal ensembles using two-photon holographic techniques requires high-sensitivity actuators to avoid photodamage and heating. Moreover, two-photon-excitable opsins should be insensitive to light at wavelengths used for imaging. To achieve this goal, we developed a novel soma-targeted variant of the large-conductance blue-light-sensitive opsin CoChR (stCoChR). In the mouse cortex in vivo, we combined holographic two-photon stimulation of stCoChR with an amplified laser tuned at the opsin absorption peak and two-photon imaging of the red-shifted indicator jRCaMP1a. Compared to previously characterized blue-light-sensitive soma-targeted opsins in vivo, stCoChR allowed neuronal stimulation with more than 10-fold lower average power and no spectral crosstalk. The combination of stCoChR, tuned amplified laser stimulation, and red-shifted functional indicators promises to be a powerful tool for large-scale interrogation of neural networks in the intact brain., Competing Interests: AF, MP, YP, OY, TF No competing interests declared, (© 2021, Forli et al.)

Perceiving the spatial location and physical dimensions of touched objects is crucial for goal-directed actions. To achieve this, our brain transforms skin-based coordinates into a reference frame by integrating visual and posture information. In the current study, we examine the role of posture in mapping tactile sensations to a visual image. We developed a new visual-to-touch sensory substitution device that transforms images into a sequence of vibrations on the arm. 52 blindfolded participants performed spatial recognition tasks in three different arm postures and had to switch postures between trial blocks. As participants were not told which side of the device is down and which is up, they could choose how to map its vertical axis in their responses. Contrary to previous findings, we show that new proprioceptive inputs can be overridden in mapping tactile sensations. We discuss the results within the context of the spatial task and the various sensory contributions to the process.

Information is carried between brain regions through neurotransmitter release from axonal presynaptic terminals. Understanding the functional roles of defined neuronal projection pathways requires temporally precise manipulation of their activity. However, existing inhibitory optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals, while chemogenetic tools are difficult to control in space and time. Here, we show that a targeting-enhanced mosquito homolog of the vertebrate encephalopsin (eOPN3) can effectively suppress synaptic transmission through the G i/o signaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutes in vitro and in vivo. In freely moving mice, eOPN3-mediated suppression of dopaminergic nigrostriatal afferents induces a reversible ipsiversive rotational bias. We conclude that eOPN3 can be used to selectively suppress neurotransmitter release at presynaptic terminals with high spatiotemporal precision, opening new avenues for functional interrogation of long-range neuronal circuits in vivo., Competing Interests: Declaration of interests O.Y. and M.M. have disclosed these findings to Yeda, the Weizmann Institute Technology Transfer Arm, which is filing a patent application on these developments. The constructs and viral vectors remain freely available from the authors and through Addgene., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Complex behavioral phenotyping techniques are becoming more prevalent in the field of behavioral neuroscience, and thus methods for manipulating neuronal activity must be adapted to fit into such paradigms. Here, we present a head-mounted, magnetically activated device for wireless optogenetic manipulation that is compact, simple to construct, and suitable for use in group-living mice in an enriched semi-natural arena over several days. Using this device, we demonstrate that repeated activation of oxytocin neurons in male mice can have different effects on pro-social and agonistic behaviors, depending on the social context. Our findings support the social salience hypothesis of oxytocin and emphasize the importance of the environment in the study of social neuromodulators. Our wireless optogenetic device can be easily adapted for use in a variety of behavioral paradigms, which are normally hindered by tethered light delivery or a limited environment., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Understanding the function of nitric oxide, a lipophilic messenger in physiological processes across nervous, cardiovascular and immune systems, is currently impeded by the dearth of tools to deliver this gaseous molecule in situ to specific cells. To address this need, we have developed iron sulfide nanoclusters that catalyse nitric oxide generation from benign sodium nitrite in the presence of modest electric fields. Locally generated nitric oxide activates the nitric oxide-sensitive cation channel, transient receptor potential vanilloid family member 1 (TRPV1), and the latency of TRPV1-mediated Ca 2+ responses can be controlled by varying the applied voltage. Integrating these electrocatalytic nanoclusters with multimaterial fibres allows nitric oxide-mediated neuronal interrogation in vivo. The in situ generation of nitric oxide in the ventral tegmental area with the electrocatalytic fibres evoked neuronal excitation in the targeted brain region and its excitatory projections. This nitric oxide generation platform may advance mechanistic studies of the role of nitric oxide in the nervous system and other organs.

Subdivisions of mouse whisker somatosensory thalamus project to cortex in a region-specific and layer-specific manner. However, a clear anatomical dissection of these pathways and their functional properties during whisker sensation is lacking. Here, we use anterograde trans-synaptic viral vectors to identify three specific thalamic subpopulations based on their connectivity with brainstem. The principal trigeminal nucleus innervates ventral posterior medial thalamus, which conveys whisker-selective tactile information to layer 4 primary somatosensory cortex that is highly sensitive to self-initiated movements. The spinal trigeminal nucleus innervates a rostral part of the posterior medial (POm) thalamus, signaling whisker-selective sensory information, as well as decision-related information during a goal-directed behavior, to layer 4 secondary somatosensory cortex. A caudal part of the POm, which apparently does not receive brainstem input, innervates layer 1 and 5A, responding with little whisker selectivity, but showing decision-related modulation. Our results suggest the existence of complementary segregated information streams to somatosensory cortices.

Decades of research support the idea that associations between a conditioned stimulus (CS) and an unconditioned stimulus (US) are encoded in the lateral amygdala (LA) during fear learning. However, direct proof for the sources of CS and US information is lacking. Definitive evidence of the LA as the primary site for cue association is also missing. Here, we show that calretinin (Calr)-expressing neurons of the lateral thalamus (Calr + LT neurons) convey the association of fast CS (tone) and US (foot shock) signals upstream from the LA in mice. Calr + LT input shapes a short-latency sensory-evoked activation pattern of the amygdala via both feedforward excitation and inhibition. Optogenetic silencing of Calr + LT input to the LA prevents auditory fear conditioning. Notably, fear conditioning drives plasticity in Calr + LT neurons, which is required for appropriate cue and contextual fear memory retrieval. Collectively, our results demonstrate that Calr + LT neurons provide integrated CS-US representations to the LA that support the formation of aversive memories.

Neurons in neocortical layer 1 (L1) are thought to regulate attentional processes through integration of long-range inputs and disinhibitory effects on the underlying cortex. A new study combines genetically targeted voltage imaging and optogenetics to elucidate the input-output transformations of the L1 network in the mouse somatosensory cortex, revealing unique features of sensory-evoked dynamics in L1 neurons., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms mediating sensory-evoked arousal remain unclear. We hypothesized that reduced locus coeruleus (LC) norepinephrine (NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological, behavioral, pharmacological, and optogenetic techniques alongside auditory stimulation in freely behaving rats. We found that systemic reduction in NE signaling lowered probability of sound-evoked awakenings (SEAs). The level of tonic LC activity during sleep anticipated SEAs. Optogenetic LC activation promoted arousal as evident in sleep-wake transitions, EEG desynchronization, and pupil dilation. Minimal LC excitation before sound presentation increased SEA probability. Optogenetic LC silencing using a soma-targeted anion-conducting channelrhodopsin (stGtACR2) suppressed LC spiking and constricted pupils. Brief periods of LC opto-silencing reduced the probability of SEAs. Thus, LC-NE activity determines the likelihood of sensory-evoked awakenings, and its reduction during sleep constitutes a key factor mediating behavioral unresponsiveness., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The prefrontal cortex (PFC) is implicated in processing of the affective state of others through non-verbal communication. This social cognitive function is thought to rely on an intact cortical neuronal excitatory and inhibitory balance. Here combining in vivo electrophysiology with a behavioral task for affective state discrimination in mice, we show a differential activation of medial PFC (mPFC) neurons during social exploration that depends on the affective state of the conspecific. Optogenetic manipulations revealed a double dissociation between the role of interneurons in social cognition. Specifically, inhibition of mPFC somatostatin (SOM + ), but not of parvalbumin (PV + ) interneurons, abolishes affective state discrimination. Accordingly, synchronized activation of mPFC SOM + interneurons selectively induces social discrimination. As visualized by in vivo single-cell microendoscopic Ca 2+ imaging, an increased synchronous activity of mPFC SOM + interneurons, guiding inhibition of pyramidal neurons, is associated with affective state discrimination. Our findings provide new insights into the neurobiological mechanisms of affective state discrimination.

Mouse primary somatosensory barrel cortex (wS1) processes whisker sensory information, receiving input from two distinct thalamic nuclei. The first-order ventral posterior medial (VPM) somatosensory thalamic nucleus most densely innervates layer 4 (L4) barrels, whereas the higher-order posterior thalamic nucleus (medial part, POm) most densely innervates L1 and L5A. We optogenetically stimulated VPM or POm axons, and recorded evoked excitatory postsynaptic potentials (EPSPs) in different cell-types across cortical layers in wS1. We found that excitatory neurons and parvalbumin-expressing inhibitory neurons received the largest EPSPs, dominated by VPM input to L4 and POm input to L5A. In contrast, somatostatin-expressing inhibitory neurons received very little input from either pathway in any layer. Vasoactive intestinal peptide-expressing inhibitory neurons received an intermediate level of excitatory input with less apparent layer-specificity. Our data help understand how wS1 neocortical microcircuits might process and integrate sensory and higher-order inputs., Competing Interests: BS, PT, MF, JM, TO, OY, JS, CP No competing interests declared, (© 2019, Sermet et al.)

Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The prefrontal cortex (PFC) plays an important role in regulating social functions in mammals, and its dysfunction has been linked to social deficits in neurodevelopmental disorders. Yet little is known of how the PFC encodes social information and how social representations may be altered in such disorders. Here, we show that neurons in the medial PFC of freely behaving male mice preferentially respond to socially relevant olfactory cues. Population activity patterns in this region differed between social and nonsocial stimuli and underwent experience-dependent refinement. In mice lacking the autism-associated gene Cntnap2, both the categorization of sensory stimuli and the refinement of social representations were impaired. Noise levels in spontaneous population activity were higher in Cntnap2 knockouts and correlated with the degree to which social representations were disrupted. Our findings elucidate the encoding of social sensory cues in the medial PFC and provide a link between altered prefrontal dynamics and autism-associated social dysfunction.

Chemogenetic techniques allow selective manipulation of neurons by activating engineered actuator proteins with otherwise inert effector molecules. A recent study (Magnus et al. Science 2019;364:eaav5282) describes the coevolution of highly potent actuator-effector pairs based on a clinically approved antismoking drug. These tools allow selective excitation or inhibition of neurons in the living brain with high specificity and no detectable side-effects., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Optogenetic silencing allows time-resolved functional interrogation of defined neuronal populations. However, the limitations of inhibitory optogenetic tools impose stringent constraints on experimental paradigms. The high light power requirement of light-driven ion pumps and their effects on intracellular ion homeostasis pose unique challenges, particularly in experiments that demand inhibition of a widespread neuronal population in vivo. Guillardia theta anion-conducting channelrhodopsins (GtACRs) are promising in this regard, due to their high single-channel conductance and favorable photon-ion stoichiometry. However, GtACRs show poor membrane targeting in mammalian cells, and the activity of such channels can cause transient excitation in the axon due to an excitatory chloride reversal potential in this compartment. Here, we address these problems by enhancing membrane targeting and subcellular compartmentalization of GtACRs. The resulting soma-targeted GtACRs show improved photocurrents, reduced axonal excitation and high light sensitivity, allowing highly efficient inhibition of neuronal activity in the mammalian brain.

Animals constantly evaluate their environment in order to avoid potential threats and obtain reward in the form of food, shelter and social interactions. In order to appropriately respond to sensory cues from the environment, the brain needs to form and store multiple cue-outcome associations. These can then be used to form predictions of the valence of sounds, smells and other sensory inputs arising from the surroundings. However, these associations must be subject to constant update, as the environment can rapidly change. Failing to adapt to such change can be detrimental to survival. Several systems in the mammalian brain have evolved to perform these important behavioral functions. Among these systems, the amygdala and prefrontal cortex are prominent players. Although the amygdala has been shown to form strong cue-outcome associations, the prefrontal cortex is essential for modifying these associations through extinction and reversal learning, and synaptic plasticity occurring in the strong reciprocal connections between these structures is thought to underlie both adaptive and maladaptive learning. Here we review the synaptic organization of the amygdala-prefrontal circuit, and summarize the physiological and behavioral evidence for its involvement in appetitive and aversive learning., (Copyright © 2018 Elsevier Ltd. All rights reserved.)