Circuit Function Research Articles

Synaptic Gα12/13 signaling establishes hippocampal PV inhibitory circuits

Combinatorial networks of cell adhesion molecules and cell surface receptors drive fundamental aspects of neural circuit establishment and function. However, the intracellular signals orchestrated by these cell surface complexes remain less understood. Here, we report that the Gα12/13 pathway lies downstream of several GPCRs with critical synaptic functions. Impairment of the Gα12/13 pathway in postnatal hippocampal neurons diminishes inhibitory inputs without altering neuronal morphology or excitatory transmission. Gα12/13 signaling in hippocampal CA1 neurons in vivo selectively regulates PV interneuron synaptic connectivity, supporting an inhibitory synapse subtype-specific function of this pathway. Our studies establish Gα12/13 as a signaling node that shapes inhibitory hippocampal circuitry.

Munir Gunes Kutlu: Exploring the neural mechanisms of learning and social behaviors – A scientist's journey and perspective

Dr. Munir “Gunes” Kutlu, Assistant Professor at the Center for Substance Abuse Research (CSAR) and the Department of Neural Sciences at Temple University Lewis Katz School of Medicine, investigates the neural mechanisms underlying associative learning, mainly focusing on reward, fear, and social interaction. Drawing from his computational neuroscience training at Duke University and postdoctoral work at Temple and Vanderbilt Universities, Dr. Kutlu combines systems neuroscience, computational approaches, and behavioral analysis to understand how our brains process environmental associations and how these processes can become maladaptive in disease states. His laboratory, dedicated to “bridging the brain-behavior gap,” fosters a collaborative environment that nurtures the next generation of neuroscientists while pursuing innovative neural circuit analysis approaches in reward and aversive learning contexts. In this Genomic Press interview, Dr. Kutlu shares his insights on these fascinating aspects of behavioral neuroscience and his laboratory's mission to advance our understanding of neural circuit function in health and disease.

Advanced Neural Probe Sensors toward Multi‐Modal Sensing and Modulation: Design, Integration, and Applications

AbstractNeural probe devices have undergone significant advancements in recent years, evolving from basic single‐functional devices to sophisticated integrated systems capable of sensing, stimulating, and regulating neural activity. The neural probes have been demonstrated as effective tools for diagnosing and treating numerous neurological disorders, as well as for understanding sophisticated connections and functions of neuron circuits. The multifunctional neural probe platforms, which combine electrical, optical, and chemical sensing capabilities, hold promising potential for revolutionizing personalized healthcare through closed‐loop neuromodulation, particularly in the treatment of conditions such as epilepsy, Parkinson's disease, and depression. Despite these advances, several challenges remain to be further investigated, including biocompatibility, long‐term signal quality and stability, and miniaturization, all of which hinder their broader clinical application. This paper provides an overview of the design principles of the neural probe structures and sensors, fabrication strategies, and integration techniques for the advanced multi‐functional neural probes. Key electrical, optical, and chemical sensing mechanisms are discussed, along with the selection of corresponding functional materials. Additionally, several representative applications are highlighted, followed by a discussion of the challenges and opportunities that lie ahead for this emerging field.

A function of TPL/TBL1-type corepressors is to nucleate the assembly of the preinitiation complex.

The plant corepressor TPL is recruited to diverse chromatin contexts, yet its mechanism of repression remains unclear. Previously, we leveraged the fact that TPL retains its function in a synthetic transcriptional circuit in the yeast model Saccharomyces cerevisiae to localize repressive function to two distinct domains. Here, we employed two unbiased whole-genome approaches to map the physical and genetic interactions of TPL at a repressed locus. We identified SPT4, SPT5, and SPT6 as necessary for repression with SPT4 acting as a bridge connecting TPL to SPT5 and SPT6. We discovered the association of multiple additional constituents of the transcriptional preinitiation complex at TPL-repressed promoters, specifically those involved early in transcription initiation. These findings were validated in yeast and plants, including a novel method to analyze the conditional loss of function of essential genes in plants. Our findings support a model where TPL nucleates preassembly of the transcription activation machinery to facilitate the rapid onset of transcription once repression is relieved.

Stimulation of Locus Ceruleus Inputs to the Prelimbic Cortex in Mice Induces Cell Type-Specific Expression of the Apoe Gene.

The medial frontal cortex (mFC) and locus ceruleus (LC) are two brain areas that have been implicated in a range of cognitive phenomena, such as attention, memory, and decision-making. Regulators of these brain regions at the molecular level are not well understood but might help to elucidate underlying mechanisms of disorders that present with deficits in these cognitive domains. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the prelimbic subregion (PrL) of the mFC and subsequent bulk RNA sequencing from the mouse PrL. We found that stimulation of this circuit caused an increase in transcription of a host of genes, including the Apoe gene. To investigate cell type-specific expression of Apoe in the PrL, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the PrL or a control virus and found that increases in Apoe expression in the PrL following depolarization of LC inputs is enriched in GABAergic neurons in a sex-dependent manner. The results of these experiments yield insights into how Apoe expression affects function in a cortical microcircuit that is important for attention, memory, and decision-making and point to interneuron-specific expression of Apoe as a potential biomarker for circuit function in disorders such as attention-deficit hyperactivity disorder, schizophrenia, and Alzheimer's disease.

One‐Step Van der Waals Integration of Multi‐Threshold 2D Functional Circuits

AbstractTransition‐metal dichalcogenides (TMDs), as atomically thin semiconductors, have shown immense promise for next‐generation electronics due to their high mobility and potential for creating van der Waals heterostructures. However, precise control of the threshold voltage (Vth) in field‐effect transistors (FETs) remains a significant challenge, impeding the development of 2D material circuits with tailored electronic functions. Herein, a graphene‐assisted one‐step van der Waals integration technique is presented for fabricating multi‐threshold 2D functional circuits. Graphene's unique property of having a surface without dangling bonds is utilized as an intermediary layer, allowing for the transfer of electrodes with various work functions and high‐κ dielectric layers onto 2D channel materials in a single step. This technique has successfully produced Al‐gated MoS2 FETs with a Vth of −0.2 V and Au‐gated MoS2 FETs with a Vth of 1.9 V. This precision enables the development of functional devices such as rail‐to‐rail inverters with large noise margins. Furthermore, more complex multi‐threshold 2D circuits are achieved, including basic logic gates (NOT, NAND, NOR), six‐transistor static random‐access memory (6T‐SRAM), and ring oscillators (RO). This work showcases a scalable and effective strategy for threshold voltage engineering in 2D material‐based circuits, paving the way for sophisticated electronic and optoelectronic applications.

Adolescent-like Processing of Behaviorally Salient Cues in Sensory and Prefrontal Cortices of Adult Preterm-Born Mice.

Preterm birth is a leading risk factor for atypicalities in cognitive and sensory processing, but it is unclear how prematurity impacts circuits that support these functions. To address this, we trained adult mice born a day early (preterm mice) on a visual discrimination task and found that they commit more errors and fail to achieve high levels of performance. Using in vivo electrophysiology , we found that the neurons in the primary visual cortex (V1) and the V1-projecting prefrontal anterior cingulate cortex (ACC) are hyper-responsive to the reward, reminiscent of cue processing in adolescence. Moreover, the non-rewarded cue fails to robustly activate the V1 and V1-projecting ACC neurons during error trials, in contrast to prefrontal fast-spiking (FS) interneurons which show elevated error-related activity, suggesting that preterm birth impairs the function of prefrontal circuits for error monitoring. Finally, environmental enrichment, a well-established paradigm that promotes sensory maturation, failed to improve the performance of preterm mice, suggesting limited capacity of early interventions for reducing the risk of cognitive deficits after preterm birth. Altogether, our study for the first time identifies potential circuit mechanisms of cognitive atypicalities in the preterm population and highlights the vulnerability of prefrontal circuits to advanced onset of extrauterine experience.

Semi-Analytical Solutions for the Qi-Type Dynamical System

The aim of present paper is to obtain approximate semi-analytical solutions for the Qi-type dynamical system, while neglecting its chaotic behaviors. These solutions are derived using the Optimal Auxiliary Functions Method (OAFM). The impact of the system’s physical parameters is also investigated. A special case, involving a constant of motion, is considered for which closed-form solutions are obtained. The dynamical system is reduced to a second-order nonlinear differential equation, which is analytically solved through the OAFM procedure. The influence of initial conditions on the system is explored, specifically regarding the presence or absence of symmetries. An exact parametric solution is obtained for a particular case. A good agreement between the analytical and corresponding numerical results is demonstrated, highlighting the accuracy of the proposed method. A comparative analysis underlines the advantages of the OAFM compared to other analytical methods. These findings have numerous technological applications, such as in nonlinear circuits with three channels that involve adapted physical parameters to ensure effective functioning of electronic circuits, as well as in information storage, encryption, and communication systems.

The gamma rhythm as a guardian of brain health.

Gamma oscillations in brain activity (30-150 Hz) have been studied for over 80 years. Although in the past three decades significant progress has been made to try to understand their functional role, a definitive answer regarding their causal implication in perception, cognition, and behavior still lies ahead of us. Here, we first review the basic neural mechanisms that give rise to gamma oscillations and then focus on two main pillars of exploration. The first pillar examines the major theories regarding their functional role in information processing in the brain, also highlighting critical viewpoints. The second pillar reviews a novel research direction that proposes a therapeutic role for gamma oscillations, namely the gamma entrainment using sensory stimulation (GENUS). We extensively discuss both the positive findings and the issues regarding reproducibility of GENUS. Going beyond the functional and therapeutic role of gamma, we propose a third pillar of exploration, where gamma, generated endogenously by cortical circuits, is essential for maintenance of healthy circuit function. We propose that four classes of interneurons, namely those expressing parvalbumin (PV), vasointestinal peptide (VIP), somatostatin (SST), and nitric oxide synthase (NOS) take advantage of endogenous gamma to perform active vasomotor control that maintains homeostasis in the neuronal tissue. According to this hypothesis, which we call GAMER (GAmma MEdiated ciRcuit maintenance), gamma oscillations act as a 'servicing' rhythm that enables efficient translation of neural activity into vascular responses that are essential for optimal neurometabolic processes. GAMER is an extension of GENUS, where endogenous rather than entrained gamma plays a fundamental role. Finally, we propose several critical experiments to test the GAMER hypothesis.

Activity-Dependent Internalization of Glun2B-Containing NMDARS Is Required For Synaptic Incorporation of Glun2A And Synaptic Plasticity.

NMDA-type glutamate receptors are heterotetrameric complexes composed of two GluN1 and two GluN2 subunits. The precise composition of the GluN2 subunits determines the channel's biophysical properties and influences its interaction with postsynaptic scaffolding proteins and signaling molecules involved in synaptic physiology and plasticity. The precise regulation of NMDAR subunit composition at synapses is crucial for proper synaptogenesis, neuronal circuit development, and synaptic plasticity, a cellular model of memory formation.In the forebrain during early development, NMDARs contain solely the GluN2B subunit, which is necessary for proper synaptogenesis and synaptic plasticity. In rodents, GluN2A subunit expression begins in the second postnatal week, replacing GluN2B-containing NMDARs at synapses in an activity- or sensory experience-dependent process. This switch in NMDAR subunit composition at synapses alters channel properties and reduces synaptic plasticity. The molecular mechanism regulating the switch remains unclear.We have investigated the role of activity-dependent internalization of GluN2B-containing receptors in shaping synaptic NMDAR subunit composition. Using molecular, pharmacological, and electrophysiological approaches in cultured organotypic hippocampal slices from rats of both sexes, we show that the process of incorporating GluN2A-containing NMDARs receptors requires activity-dependent internalization of GluN2B-containing NMDARs. Interestingly, blockade of GluN2A synaptic incorporation was associated with impaired potentiation of AMPA-mediated synaptic transmission, suggesting a potential coupling between the trafficking of AMPARs into synapses and that of GluN2A-containing NMDARs.These insights contribute to our understanding of the molecular mechanisms underlying synaptic trafficking of glutamate receptors and synaptic plasticity. They may also have implications for therapeutic strategies targeting NMDAR function in neurological disorders.Significance statement NMDARs play a critical role in synaptogenesis, synaptic stability, and activity-dependent regulation of synaptic strength. The developmental switch in their GluN2 subunits composition is part of normal synapse development and crucial for proper synaptic physiology, plasticity, and the formation of functional neuronal circuits, though the mechanisms governing it remain unclear. We show that internalization of GluN2B-containing NMDARs is required for synaptic incorporation of GluN2A-containing receptors. This process can be induced by long-term potentiation and requires Ca+2 Notably, GluN2A trafficking to synapses is linked to the incorporation of AMPA-type glutamate receptors, suggesting a shared pathway for synaptic incorporation. These findings provide greater insight into the molecular mechanisms behind glutamate receptor trafficking and synaptic plasticity, potentially informing therapeutic strategies for neurological disorders.

Retinal ganglion cell-derived semaphorin 6A segregates starburst amacrine cell dendritic scaffolds to organize the mouse inner retina.

To form functional circuits, neurons must settle in their appropriate cellular locations, and then project and elaborate neurites to contact their target synaptic neuropils. Laminar organization within the vertebrate retinal inner plexiform layer (IPL) facilitates pre- and postsynaptic neurite targeting, yet the precise mechanisms underlying establishment of functional IPL subdomains are not well understood. Here, we explore mechanisms defining the compartmentalization of OFF and ON neurites generally, and OFF and ON direction-selective neurites specifically, within the developing mouse IPL. We show that semaphorin 6A (Sema6A), a repulsive axon guidance cue, is required for delineation of OFF versus ON circuits within the IPL: in the Sema6a null IPL, the boundary between OFF and ON domains is blurred. Furthermore, Sema6A expressed by retinal ganglion cells (RGCs) directs laminar segregation of OFF and ON starburst amacrine cell dendritic scaffolds, which themselves serve as a substrate upon which other retinal neurites elaborate. These results demonstrate that RGCs, the first type of neuron born within the retina, play an active role in functional specialization of the IPL.

A New Multicommodity Network Flow Model and Branch and Cut for Optimal Quantum Boolean Circuit Synthesis

This study introduces a new optimization model and a branch-and-cut approach for synthesizing optimal quantum circuits for reversible Boolean functions, which are pivotal components in quantum algorithms. Although heuristic algorithms have been extensively explored for quantum circuit synthesis, research on exact counterparts remains relatively limited. However, the need to design quantum circuits with guaranteed optimality is increasing, especially for improving computational fidelity on noisy intermediate-scale quantum devices. This study presents mathematical optimization as a viable option for optimal synthesis, with the potential to accommodate practical considerations arising in fast-evolving quantum technologies. We set a demonstrative problem to implement reversible Boolean functions using high-level gates known as multiple control Toffoli gates while minimizing a technology-based proxy called quantum cost—the number of low-level gates used to realize each high-level gate. To address this problem, we propose a discrete optimization model based on a multicommodity network and discuss potential future variations at an abstract level to incorporate technical considerations. A customized branch and cut is then developed upon different aspects of our model, including polyhedron integrality, surrogate constraints, and variable prioritization. Our experiments demonstrate the robustness of the proposed approach in finding cost-optimal circuits for all benchmark instances within a two-hour time frame. Furthermore, we present interesting intuitions from these experiments and compare our computational results with relevant studies, highlighting newly discovered circuits with the lowest quantum costs reported in this paper. History: Accepted by Giacomo Nannicini, Area Editor for Quantum Computing. This paper has been accepted for the INFORMS Journal on Computing Special Issue on Quantum Computing. Funding: This research was supported by the Ministry of Science and Information and Communication Technology, South Korea [Grants 2017R1E1A1A0307098814 and 2020R1A4A307986411]. Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2024.0562 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2024.0562 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .

A positive feedback loop of SRSF9/USP22/ZEB1 promotes the progression of ovarian cancer

ABSTRACT Ovarian cancer (OC) is recognized as the most lethal type of gynecological malignancy, making treatment options challenging. Discovering novel therapeutic targets will benefit OC patients. This study aimed to reveal the mechanism by which SRSF9 regulates OC progression. Cell proliferation was determined via CCK-8 assays, whereas cell migration and invasion were monitored via Transwell assays. Western blotting and qPCR assays were used to detect protein and mRNA alterations. RNA pull-down, RNA immunoprecipitation (RIP), and actinomycin D experiments were performed to investigate the relationships between SRSF9 and USP22. Co-IP was used to validate the interaction between USP22 and ZEB1. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to verify the regulatory effect of ZEB1 on the transcription of SRSF9. Subcutaneous xenograft models were established to evaluate the impact of SRSF9 on tumor development. Knockdown of SRSF9 significantly suppressed the proliferation, invasion, migration, tumorigenicity, and epithelial‒mesenchymal transition (EMT) of OC cells. SRSF9 can bind to USP22 mRNA, increasing its stability. Moreover, the overexpression of USP22 reversed the impact of SRSF9 silencing on malignant phenotypes. USP22 can mediate the deubiquitination of ZEB1, thereby enhancing the progression of OC. Furthermore, ZEB1 upregulated SRSF9 expression through transcriptional activation, thus establishing a positive feedback loop. SRSF9 enhanced the malignant characteristics of OC through a positive feedback loop of SRSF9/USP22/ZEB1. This functional circuit may help in the development of novel therapeutic approaches for treating OC.

Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system.

Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by a highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity with >40 causative genes that encode proteins localising to the primary cilium, a sensory organelle that is essential for transduction of signalling pathways during neurodevelopment, among other vital functions. JBTS proteins localise to distinct ciliary subcompartments, suggesting diverse functions in cilium biology. Currently, there is no unifying pathomechanism to explain how dysfunction of such diverse primary cilia-related proteins results in such a highly specific brain abnormality. In order to identify the shared consequence of JBTS gene dysfunction, we carried out transcriptomic analysis using zebrafish mutants for the JBTS-causative genes cc2d2aw38, cep290fh297, inpp5ezh506, talpid3i264 and togaram1zh510and the Bardet-Biedl syndrome-causative gene bbs1k742. We identified no commonly dysregulated signalling pathways in these mutants and yet all mutants displayed an enrichment of altered gene sets related to central nervous system function. We found that JBTS mutants have altered primary cilia throughout the brain, however do not display abnormal brain morphology. Nonetheless, behavioural analyses revealed reduced locomotion and loss of postural control which, together with the transcriptomic results, hint at underlying abnormalities in neuronal activity and/or neuronal circuit function. These zebrafish models therefore offer the unique opportunity to study the role of primary cilia in neuronal function beyond early patterning, proliferation and differentiation.

Amplifier gain exploration: Technical or structural means of enhancing the gain of an amplifier

Abstract. The primary function of an amplification circuit is to amplify the input dynamic signal without distortion. Therefore, there is aproportional relationship between the output and input signals, which is referred to as gain. Gain, the ratio of output voltage to input voltage, is a crucial performance metric for amplifiers and plays a vital role in electronic circuits. Amplifiers are now an indispensable part of various fields. Amplifier circuit structures vary widely, and different amplification circuits are used in different applications and fields due to their unique advantages and inevitable drawbacks. Practically, it is necessary to maximize strengths and minimize weaknesses by sele cting the most suitable amplification circuit. This paper analyzes several typical structural methods for enhancing amplifier gain and discusses the advantages and disadvantages of each structure. Through theoretical derivation and Cadence software simulation, it is demonstrated that the cascode, five-transistor OTA structure, and cascade structure play important roles in achieving circuit gain.

Projection-specific circuits of retrosplenial cortex with differential contributions to spatial cognition.

Retrosplenial cortex (RSC) is a brain region involved in neuropsychiatric and neurodegenerative disorders. It has reciprocal connections with a diverse set of cortical and subcortical brain regions, but the afferent structure and behavioral function of circuits defined by its projection-specific sub-populations have yet to be determined. The corticocortical connections between RSC and secondary motor cortex (M2), as well as corticothalamic connections between RSC and anterodorsal thalamus (AD) have been hypothesized to function as semi-independent, but parallel pathways that impact spatial information processing in distinct ways. We used retrograde and anterograde viral tracers and monosynaptic retrograde rabies virus to quantitatively characterize and compare the afferent and efferent distributions of retrosplenial neuron sub-populations projecting to M2 and AD. AD-projecting and M2-projecting RSC neurons overlap in their collateral projections to other brain regions, but not in their projections to M2 and AD, respectively. Compared with AD-projecting RSC neurons, M2-projecting RSC neurons received much greater afferent input from the dorsal subiculum, AD, lateral dorsal and lateral posterior thalamus, and somatosensory cortex. AD-projecting RSC neurons received greater input from the anterior cingulate cortex and medial septum. We performed chemogenetic inhibition of M2- and AD-projecting RSC neurons and examined its impact on object-location memory, object-recognition, open-field exploration, and place-action association. Our findings indicate that inhibition of M2-projecting RSC neurons impairs object location memory as well as place-action association, while the RSC to AD pathway impacts only object-location memory. The findings indicate that RSC is composed of semi-independent circuits distinguishable by their afferent/efferent distributions and differing in the cognitive functions to which they contribute.

Nucleic acid sensing in the central nervous system: Implications for neural circuit development, function, and degeneration.

Nucleic acids are a critical trigger for the innate immune response to infection, wherein pathogen-derived RNA and DNA are sensed by nucleic acid sensing receptors. This subsequently drives the production of type I interferon and other inflammatory cytokines to combat infection. While the system is designed such that these receptors should specifically recognize pathogen-derived nucleic acids, it is now clear that self-derived RNA and DNA can also stimulate these receptors to cause aberrant inflammation and autoimmune disease. Intriguingly, similar pathways are now emerging in the central nervous system in neurons and glial cells. As in the periphery, these signaling pathways are active in neurons and glia to present the spread of pathogens in the CNS. They further appear to be active even under steady conditions to regulate neuronal development and function, and they can become activated aberrantly during disease to propagate neuroinflammation and neurodegeneration. Here, we review the emerging new roles for nucleic acid sensing mechanisms in the CNS and raise open questions that we are poised to explore in the future.

Single-crystal ferroelectric LiNbO3 thin film-based synaptic devices enabled with tunable domain wall current for neuromorphic computing

Neuromorphic devices can emulate the human brain to process information, which receives lots of attention in the field of artificial intelligence. Synaptic devices based on ferroelectric thin films feature low-power consumption, multifunctionality, and scalability. Among them, ferroelectric charged domain wall (CDW) devices have attracted intensive interest for the implementation of memristive devices due to their ultrahigh integration ability inherited from the nanoscale domain wall thickness. In particular, the preparation of wafer-scale single-crystalline ferroelectric thin films via ion-sliced heterogeneous wafer bonding lays a good foundation for large-scale integration of ferroelectric devices with functional circuits. However, the biomimic synaptic characteristics and the systematic demonstration of synaptic devices are largely unexplored for this material system. Here, we demonstrate a model synaptic device based on a single-crystal ferroelectric LiNbO3 thin film, which provides the desired characteristics for neuromorphic computing. The conductance modulation demonstrates good linearity for efficient neuromorphic computing applications. Simulations using the Modified National Institute of Standards and Technology handwritten recognition dataset prove that LiNbO3-based synaptic devices can operate with an online learning accuracy of 95.1%. The injection and annihilation of the CDW are proposed as the basis of the conductivity modulation by combining with the piezoresponse force microscopy and conductive atomic force microscopy mapping measurements. With the mature fabrication process of the ultrathin high-quality ferroelectric thin films, LiNbO3-based synaptic devices have an extensive application prospect for future neuromorphic computing systems.

Phase Separation to Resolve Growth-Related Circuit Failures.

Fluctuations in host cell growth poses a significant challenge to synthetic gene circuits, often disrupting circuit function. Existing solutions typically rely on circuit redesign with alternative topologies or additional control elements, yet a broadly applicable approach remains elusive. Here, we introduce a new strategy based on liquid-liquid phase separation (LLPS) to stabilize circuit performance. By engineering a self-activating circuit with transcription factors (TF) fused to an intrinsically disordered region (IDR), we enable the formation of TF condensates at the promoter region, maintaining local TF concentration despite growth-mediated dilution. This condensate formation preserves bistable memory in the self-activating circuit, demonstrating that phase separation can robustly counteract growth fluctuations, offering a novel design principle for resilient synthetic circuits.

Transcutaneous spinal cord stimulation neuromodulates pre- and postsynaptic inhibition in the control of spinal spasticity

Aside from enabling voluntary control over paralyzed muscles, a key effect of spinal cord stimulation is the alleviation of spasticity. Dysfunction of spinal inhibitory circuits is considered a major cause of spasticity. These circuits are contacted by Ia muscle spindle afferents, which are also the primary targets of transcutaneous lumbar spinal cord stimulation (TSCS). We hypothesize that TSCS controls spasticity by transiently strengthening spinal inhibitory circuit function through their Ia-mediated activation. We show that 30min of antispasticity TSCS improves activity in post- and presynaptic inhibitory circuits beyond the intervention in ten individuals with traumatic spinal cord injury to normative levels established in 20 neurologically intact individuals. These changes in circuit function correlate with improvements in muscle hypertonia, spasms, and clonus. Our study opens the black box of the carryover effects of antispasticity TSCS and underpins a causal role of deficient post- and presynaptic inhibitory circuits in spinal spasticity.