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A psychotherapeutic regimen that uses alternating bilateral sensory stimulation (ABS) has been used to treat post-traumatic stress disorder. However, the neural basis that underlies the long-lasting effect of this treatment—described as eye movement desensitization and reprocessing—has not been identified. Here we describe a neuronal pathway driven by the superior colliculus (SC) that mediates persistent attenuation of fear. We successfully induced a lasting reduction in fear in mice by pairing visual ABS with conditioned stimuli during fear extinction. Among the types of visual stimulation tested, ABS provided the strongest fear-reducing effect and yielded sustained increases in the activities of the SC and mediodorsal thalamus (MD). Optogenetic manipulation revealed that the SC–MD circuit was necessary and sufficient to prevent the return of fear. ABS suppressed the activity of fear-encoding cells and stabilized inhibitory neurotransmission in the basolateral amygdala through a feedforward inhibitory circuit from the MD. Together, these results reveal the neural circuit that underlies an effective strategy for sustainably attenuating traumatic memories. Bilateral sensory stimulation, which is used to treat post-traumatic stress disorder in humans, alleviates fear memory in mice through a circuit involving the superior colliculus and the medial thalamus.

Prior experience of social hierarchy is known to modulate emotional contagion, a basic form of affective empathy. However, it is not known whether this behavioral effect occurs through changes in an individual's traits due to their experience of social hierarchy or specific social interrelationships between the individuals. Groups of four mice with an established in‐group hierarchy were used to address this in conjunction with a tube test. The rank‐1 and rank‐4 mice were designated as the dominant or subordinate groups, respectively. The two individuals in between were designated as the intermediate groups, which were then used as the observers in observational fear learning (OFL) experiments, an assay for emotional contagion. The intermediate observers showed greater OFL responses to the dominant demonstrator than the subordinate demonstrators recruited from the same home‐cage. When the demonstrators were strangers from different cages, the intermediate observers did not distinguish between dominant and subordinate, displaying the same level of OFL. In a reverse setting in which the intermediate group was used as the demonstrator, the subordinate observers showed higher OFL responses than the dominant observers, and this occurred only when the demonstrators were cagemates of the observers. Furthermore, the bigger the rank difference between a pair, the higher the OFL level that the observer displayed. Altogether, these results demonstrate that the hierarchical interrelationship established between a given pair of animals is critical for expressing emotional contagion between them rather than any potential changes in intrinsic traits due to the experience of dominant/subordinate hierarchy. Practitioner points Subordinate observer or dominant demonstrator resulted in higher affective empathic response in familiar pairs but not unfamiliar pairs. The relative social rank of the observer with respect to the demonstrator had a negative linear correlation with the affective empathic response of the observer in familiar pairs but not unfamiliar pairs. The effect of social rank on affective empathy is attributed to the prior social hierarchical interrelationship between them and is not due to intrinsic attributes of an individual based on one's dominance rank. Subordinate observer or dominant demonstrator resulted in higher empathic response in familiar pair. The hierarchical effect on empathy was not observed toward an unfamiliar partner. The relative hierarchy is sufficient to distinguish the difference in empathy.

Fear can be induced either directly through self-experience of aversive events or vicariously by observing conspecifics experiencing such events. The locus coeruleus-norepinephrine (LC-NA) system is crucial in fear responses and cognitive processes. We investigated whether the LC-NA system differentially processes these two types of fear, direct and vicarious in male mice. The results highlighted that the right hemisphere LC→anterior cingulate cortex pathway is uniquely crucial for vicarious fear, while the two inputs to the LC—from the bed nucleus of the stria terminalis (BNST) and the central amygdala (CeA)—differentially contribute to fear processing. The BNST plays a more targeted role in vicarious fear, and the CeA has a broader influence on fear in general. This underscores the complexity and specialization within the LC-NA system for fear-processing. Fear arises directly or vicariously, with the LC-NA system involved in both. Here, the authors show that the right LC → ACC pathway is key for vicarious fear, while BNST and CeA provide distinct inputs to LC, highlighting its complex role in fear.

Mammalian brain glycome remains a relatively poorly understood area compared to other large-scale “omics” studies, such as genomics and transcriptomics due to the inherent complexity and heterogeneity of glycan structure and properties. Here,we first performed spatial and temporal analysis of glycome expression patterns in the mammalian brain using a cutting-edge experimental tool based on liquid chromatography-mass spectrometry, with the ultimate aim to yield valuable implications on molecular events regarding brain functions and development. We observed an apparent diversity in the glycome expression patterns, which is spatially well-preserved among nine different brain regions in mouse. Next, we explored whether the glycome expression pattern changes temporally during postnatal brain development by examining the prefrontal cortex (PFC) at different time point across six postnatal stages in mouse. We found that glycan expression profiles were dynamically regulated during postnatal developments. A similar result was obtained in PFC samples from humans ranging in age from 39 d to 49 y. Novel glycans unique to the brain were also identified. Interestingly, changes primarily attributed to sialylated and fucosylated glycans were extensively observed during PFC development. Finally, based on the vast heterogeneity of glycans, we constructed a core glyco-synthesis map to delineate the glycosylation pathway responsible for the glycan diversity during the PFC development. Our findings reveal high levels of diversity in a glycosylation program underlying brain region specificity and age dependency, and may lead to new studies exploring the role of glycans in spatiotemporally diverse brain functions.

Thermal sensations contribute to our ability to perceive and explore the physical world. Reproducing these sensations in a spatiotemporally programmable manner through wireless computer control could enhance virtual experiences beyond those supported by video, audio and, increasingly, haptic inputs. Flexible, lightweight and thin devices that deliver patterns of thermal stimulation across large areas of the skin at any location of the body are of great interest in this context. Applications range from those in gaming and remote socioemotional communications, to medical therapies and physical rehabilitation. Here, we present a set of ideas that form the foundations of a skin-integrated technology for power-efficient generation of thermal sensations across the skin, with real-time, closed-loop control. The systems exploit passive cooling mechanisms, actively switchable thermal barrier interfaces, thin resistive heaters and flexible electronics configured in a pixelated layout with wireless interfaces to portable devices, the internet and cloud data infrastructure. Systematic experimental studies and simulation results explore the essential mechanisms and guide the selection of optimized choices in design. Demonstration examples with human subjects feature active thermoregulation, virtual social interactions, and sensory expansion.

Synaptic inhibition is based on both tonic and phasic release of the inhibitory transmitter γ-aminobutyric acid (GABA). Although phasic GABA release arises from Ca²⁺-dependent exocytosis from neurons, the mechanism of tonic GABA release is unclear. Here we report that tonic inhibition in the cerebellum is due to GABA being released from glial cells by permeation through the Bestrophin 1 (Best1) anion channel. We demonstrate that GABA directly permeates through Best1 to yield GABA release and that tonic inhibition is eliminated by silencing of Best1. Glial cells express both GABA and Best1, and selective expression of Best1 in glial cells, after preventing general expression of Best1, fully rescues tonic inhibition. Our results identify a molecular mechanism for tonic inhibition and establish a role for interactions between glia and neurons in mediating tonic inhibition.

Spatiotemporal control of gene expression or labeling is a valuable strategy for identifying functions of genes within complex neural circuits. Here, we develop a highly light-sensitive and efficient photoactivatable Flp recombinase (PA-Flp) that is suitable for genetic manipulation in vivo. The highly light-sensitive property of PA-Flp is ideal for activation in deep mouse brain regions by illumination with a noninvasive light-emitting diode. In addition, PA-Flp can be extended to the Cre-lox system through a viral vector as Flp-dependent Cre expression platform, thereby activating both Flp and Cre. Finally, we demonstrate that PA-Flp–dependent, Cre-mediated Ca v 3.1 silencing in the medial septum increases object-exploration behavior in mice. Thus, PA-Flp is a noninvasive, highly efficient, and easy-to-use optogenetic module that offers a side-effect-free and expandable genetic manipulation tool for neuroscience research. Most approaches to control gene expression in vivo require generation of knock-in mouse lines and often lack spatiotemporal control. Here the authors develop a photo-activatable Flp recombinase system and demonstrate its use by controlling object-exploration behavior in mice through Cav3.1 silencing.

Haptic interfaces can be used to add sensations of touch to virtual and augmented reality experiences. Soft, flexible devices that deliver spatiotemporal patterns of touch across the body, potentially with full-body coverage, are of particular interest for a range of applications in medicine, sports and gaming. Here we report a wireless haptic interface of this type, with the ability to display vibro-tactile patterns across large areas of the skin in single units or through a wirelessly coordinated collection of them. The lightweight and flexible designs of these systems incorporate arrays of vibro-haptic actuators at a density of 0.73 actuators per square centimetre, which exceeds the two-point discrimination threshold for mechanical sensation on the skin across nearly all the regions of the body except the hands and face. A range of vibrant sensations and information content can be passed to mechanoreceptors in the skin via time-dependent patterns and amplitudes of actuation controlled through the pressure-sensitive touchscreens of smart devices, in real-time with negligible latency. We show that this technology can be used to convey navigation instructions, to translate musical tracks into tactile patterns and to support sensory replacement feedback for the control of robotic prosthetics. A lightweight, flexible technology that displays vibro-tactile patterns across large areas of the skin in single units or through a wirelessly coordinated collection of them can be used to convey map directions for road navigation, translate musical tracks into tactile patterns and reconstruct tactile sensations for feedback control of robotic prosthetics.

Gangliosides in the brain play a crucial role in modulating the integrity of vertebrate central nervous system in a region-specific manner. However, to date, a comprehensive structural elucidation of complex intact ganglioside isomers has not been achieved, resulting in the elusiveness into related molecular mechanism. Here, we present a glycolipidomic approach for isomer-specific and brain region-specific profiling of the mouse brain. Considerable region-specificity and commonality in specific group of regions are highlighted. Notably, we observe a similarity in the abundance of major isomers, GD1a and GD1b, within certain regions, which provides significant biological implications with interpretation through the lens of a theoretical retrosynthetic state-transition network. Furthermore, A glycocentric-omics approaches using gangliosides and N-glycans reveal a remarkable convergence in spatial dynamics, providing valuable insight into molecular interaction network. Collectively, this study uncovers the spatial dynamics of intact glyco-conjugates in the brain, which are relevant to regional function and accelerates the discovery of potential therapeutic targets for brain diseases. Gangliosides are vital for brain function, but their isomer-specific investigations are limited. Here, the authors use a glyco-lipidomic approach to profile ganglioside isomers and N-glycans in mouse brain regions, revealing regional specificity and commonality.

Optogenetic approaches for controlling Ca 2+ channels provide powerful means for modulating diverse Ca 2+ -specific biological events in space and time. However, blue light-responsive photoreceptors are, in principle, considered inadequate for deep tissue stimulation unless accompanied by optic fiber insertion. Here, we present an ultra-light-sensitive optogenetic Ca 2+ modulator, named monSTIM1 encompassing engineered cryptochrome2 for manipulating Ca 2+ signaling in the brain of awake mice through non-invasive light delivery. Activation of monSTIM1 in either excitatory neurons or astrocytes of mice brain is able to induce Ca 2+ -dependent gene expression without any mechanical damage in the brain. Furthermore, we demonstrate that non-invasive Ca 2+ modulation in neurons can be sufficiently and effectively translated into changes in behavioral phenotypes of awake mice. Optogenetic applications in the brain of live animals often require the use of optic fibers due to poor tissue-penetration of blue light. Here the authors present monSTIM1, an improved high sensitivity optogenetic tool able to modulate Ca 2+ signaling in the brain of awake mice using non-invasive light stimulation.