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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2025

Thalamus-cortex interactions drive cell type-specific cortical development in human pluripotent stem cell-derived assembloids

The thalamus plays a pivotal role in the development and function of neural circuits in the cerebral cortex. However, how thalamus-cortex interactions influence human cortical development remains unknown primarily because of the inaccessibility of the human embryonic brain. Here, we demonstrate thalamus-dependent gene expression, circuit organization, and neural activity during corticogenesis using human thalamocortical assembloids (hThCAs). Human cortical and thalamic organoids (hCOs and hThOs) derived from induced pluripotent stem cells exhibited region-specific gene expression and spontaneous neuronal activity. Upon the fusion of these organoids, hThCAs reconstructed reciprocal thalamus-cortex axonal projections and synaptic connections. Transcriptomic analysis revealed thalamus-dependent acceleration of cortical maturation, with upregulation of programs linked to axon development, subplate/cortical plate identity, and activity-regulated genes. Histological analysis showed expanded progenitor pools and increased deep-layer neurons within hThCAs. Wide-field Ca2+ imaging demonstrated that wave-like activity originated in the thalamic region and propagated to the cortical region. Furthermore, two-photon Ca2+ imaging of cortical neurons revealed that synchronous activity emerged exclusively in pyramidal tract (PT) and corticothalamic (CT) neurons, whereas intratelencephalic (IT) neurons remain asynchronous, highlighting cell type-specific circuit integration within hThCAs. These synchronized events were absent in isolated hCOs or in cortico-cortical assembloids, underscoring the specificity of thalamic input. Our findings suggest that diffusible thalamic cues broadly enhance progenitor expansion, while long-range thalamic input organizes cell type-specific synchronous activity. This study demonstrates the thalamus-dependent acquisition of mature cortical phenotypes in a cell type-specific manner in hThCAs, establishing developmental mechanisms linking regional interactions and cell type-specific circuit specification. Thus, hThCAs provide a tractable human platform for dissecting human-specific developmental processes and modeling neurodevelopmental disorders with disrupted thalamocortical communication at the molecular, cellular, and circuit levels. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/681772v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@95b599org.highwire.dtl.DTLVardef@c56085org.highwire.dtl.DTLVardef@43df08org.highwire.dtl.DTLVardef@1e7c4ed_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIhThCAs recapitulate the developmental sequence of reciprocal projections with synapses. C_LIO_LIhThCA cortical transcriptomes resemble the late fetal human cortex. C_LIO_LIThalamic paracrine signals promote progenitor expansion and cortical cytoarchitecture. C_LIO_LIWave-like activity originates in the thalamus and propagates across the cortex. C_LIO_LIThalamic input drives cell type-specific synchronization and circuit integration. C_LI

neuroscience↗

bioRxiv2020

Cellular expression and functional roles of all 26 neurotransmitter GPCRs in the C. elegans egg-laying circuit

Maps of the synapses made and neurotransmitters released by all neurons in model systems such as C. elegans have left still unresolved how neural circuits integrate and respond to neurotransmitter signals. Using the egg-laying circuit of C. elegans as a model, we mapped which cells express each of the 26 neurotransmitter G protein coupled receptors (GPCRs) of this organism and also genetically analyzed the functions of all 26 GPCRs. We found that individual neurons express many distinct receptors, epithelial cells often express neurotransmitter receptors, and receptors are often positioned to receive extrasynaptic signals. The egg-laying circuit appears to use redundancy and compensation to achieve functional robustness, as receptor knockouts reveal few defects; however, increasing receptor signaling through overexpression more efficiently reveals receptor functions. This map of neurotransmitter GPCR expression and function in the egg-laying circuit provides a model for understanding GPCR signaling in other neural circuits.

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bioRxiv2020

Decoding music-evoked emotions in the auditory and motor cortex

Music can induce strong subjective experience of emotions, but it is debated whether these responses engage the same neural circuits as emotions elicited by biologically significant events. We examined the functional neural basis of music-induced emotions in a large sample (n=102) of subjects who listened to emotionally engaging (happy, sad, fearful, and tender) pieces of instrumental music while their haemodynamic brain activity was measured with functional magnetic resonance imaging (fMRI). Ratings of the four categorical emotions and liking were used to predict haemodynamic responses in general linear model (GLM) analysis of the fMRI data. Multivariate pattern analysis (MVPA) was used to reveal discrete neural signatures of the four categories of music-induced emotions. To map neural circuits governing non-musical emotions, the subjects were scanned while viewing short emotionally evocative film clips. The GLM revealed that most emotions were associated with activity in the auditory, somatosensory and motor cortices, cingulate gyrus, insula, and precuneus. Fear and liking also engaged the amygdala. In contrast, the film clips strongly activated limbic and cortical regions implicated in emotional processing. MVPA revealed that activity in the auditory cortex in particular as well as in the primary motor cortices reliably discriminated the emotion categories. Our results indicate that different music-induced basic emotions have distinct representations in regions supporting auditory processing, motor control, somatosensation and interoception but do not strongly rely on limbic and medial prefrontal regions critical for emotions with survival value.

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bioRxiv2022

Botulinum neurotoxin accurately separates tonic vs phasic transmission and reveals heterosynaptic plasticity rules in Drosophila

In developing and mature nervous systems, diverse neuronal subtypes innervate common targets to establish and maintain functional neural circuits. A major challenge towards understanding the structural and functional architecture of neural circuits is to separate these inputs and determine their intrinsic and heterosynaptic relationships. The Drosophila larval neuromuscular junction is a powerful model system to study these questions, where two glutamatergic motor neurons, the strong phasic-like Is and weak tonic-like Ib, co-innervate individual muscle targets to coordinate locomotor behavior. However, complete neurotransmission from each input has never been electrophysiologically separated. We have developed a botulinum neurotoxin, BoNT-C, that eliminates both spontaneous and evoked neurotransmission without perturbing synaptic growth or structure, enabling the first approach that accurately isolates input-specific neurotransmission. Selective expression of BoNT-C in Is or Ib motor inputs disambiguates functional properties of each input. Importantly, the composite values of Is and Ib neurotransmission can be fully recapitulated by isolated physiology from each input. Finally, selective silencing by BoNT-C does not induce heterosynaptic structural or functional plasticity at the convergent input. Thus, BoNT-C establishes the first approach to cleanly separate neurotransmission between tonic vs phasic neurons and defines heterosynaptic plasticity rules in a powerful model glutamatergic circuit.

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bioRxiv2022

Functional connectivity between interoceptive brain regions is associated with distinct health-related domains - a population-based neuroimaging study

Interoception is the sensation, perception, and control of signals from within the body. It has been associated with a broad range of physiological and psychological processes. Further, interoceptive variables are related to specific regions and networks in the human brain. However, it is not clear whether or how these networks relate empirically to different domains of physiological and psychological health at the population level. We analysed a dataset of 19 020 individuals (10 055 females, 8 965 males; mean age: 63 years, age range: 45 - 81 years), who have participated in the UK Biobank Study, a very large scale prospective epidemiological health study. Using canonical correlation analysis (CCA), allowing for the examination of associations between two sets of variables, we related the functional connectome of brain regions implicated in interoception to a selection of non-imaging health and lifestyle related phenotypes, exploring their relationship within modes of population co-variation. In one integrated and data driven analysis, we obtained four statistically significant modes. Modes could be categorised into domains of affect and cardiovascular health, breathing, obesity, and subjective health (all p < 0.0001) and were meaningfully associated with distinct neural circuits. Circuits represent specific neural "fingerprints" of functional domains and set the scope for future studies on the neurobiology of interoceptive involvement in different lifestyle and health related phenotypes. Therefore, our research contributes to the conceptualisation of interoception and may lead to a better understanding of co-morbid conditions in the light of shared interoceptive structures.

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bioRxiv2022

Causal contributions to sensory-based decision-making by cell-type specific circuits in the tail striatum

The striatum comprises distinct types of neurons giving rise to the direct and indirect basal ganglia pathways and local circuits. A large amount of work has been focusing on cell-type specific striatal circuits in the context of movement control, proposing several models on their functional roles. But it remains to be elucidated how the cell-type specific striatal circuits contribute to decision-making behavior and whether the existing models apply. Here, we investigate the causal roles of the cell-type specific circuits in the posterior tail of the dorsal striatum (TS) of mice in an auditory-guided decision-making behavior. Transient unilateral activation of the direct- or indirect-pathway striatal spiny projection neurons (dSPNs or iSPNs) both biased decisions in opposite directions. These effects, however, were not due to a direct influence on movement, but was specific to the decision period preceding action execution. Optogenetic inactivation of dSPNs and iSPNs revealed their opposing causal contributions to decisions. At the local circuit level, simutaneous optical recording and manipulation of dSPNs and iSPNs revealed their antagnizing interactions. Inactivation of PV interneurons, a common inhibitory input to both dSPNs and iSPNs, facilitated contraversive choices, supporting a causal contribution of coordinated striatal circuits. Using a neural circuit model, we further demonstrated the computational implemenation of the causal circuit mechanism. Our results indicate that while the causal roles of the cell-type specific striatal circuits in decision-making largely agree with classic models in movement control, they show decision task-related specificity involving local circuit coordination.

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bioRxiv2022

Why is the perceptual octave stretched? An account based on mismatched time constants within the auditory brainstem.

This paper suggests an explanation for listeners greater tolerance to positive than negative mistuning of the higher tone within an octave pair. It hypothesizes a neural circuit tuned to cancel the lower tone, that also cancels the higher tone if that tone is in tune. Imperfect cancellation is the cue to mistuning of the octave. The circuit involves two neural pathways, one delayed with respect to the other, that feed a coincidence-sensitive neuron via excitatory and inhibitory synapses. A mismatch between the time constants of these two synapses results in an asymmetry in sensitivity to mismatch. Specifically, if the time constant of the delayed pathway is greater than that of the direct pathway, there is a greater tolerance to positive mistuning than to negative mistuning. The model is directly applicable to the harmonic octave (concurrent tones), but extending it to the melodic octave (successive tones) requires additional assumptions that are discussed. The paper reviews evidence from auditory psychophysics and physiology in favor - or against - this explanation.

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bioRxiv2023

Temporal dynamics of Na/K pump mediated memory traces: insights from conductance-based models of Drosophila neurons

Sodium potassium ATPases (Na/K pumps) mediate long-lasting, dynamic cellular memories that can last tens of seconds. The mechanisms controlling the dynamics of this type of cellular memory are not well understood and can be counterintuitive. Here, we use computational modeling to examine how Na/K pumps and the ion concentration dynamics they influence shape cellular excitability. In a Drosophila larval motor neuron model, we incorporate a Na/K pump, a dynamic intracellular Na+ concentration, and a dynamic Na+ reversal potential. We probe neuronal excitability with a variety of stimuli, including step currents, ramp currents, and zap currents, then monitor the sub- and suprathreshold voltage responses on a range of time scales. We find that the interactions of a Na+-dependent pump current with a dynamic Na+ concentration and reversal potential endow the neuron with rich response properties that are absent when the role of the pump is reduced to the maintenance of constant ion concentration gradients. In particular, these dynamic pump-Na+ interactions contribute to spike rate adaptation and result in long-lasting excitability changes after spiking and even after sub-threshold voltage fluctuations on multiple time scales. We further show that modulation of pump properties can profoundly alter a neurons spontaneous activity and response to stimuli by providing a mechanism for bursting oscillations. Our work has implications for experimental studies and computational modeling of the role of Na/K pumps in neuronal activity, information processing in neural circuits and the neural control of animal behavior.

neuroscience↗

bioRxiv2023

Separating cognitive and motor processes in the behaving mouse

The cognitive processes supporting complex animal behavior are closely associated with ubiquitous movements responsible for our posture, facial expressions, ability to actively sample our sensory environments, and other critical processes. These movements are strongly related to neural activity across much of the brain and are often highly correlated with ongoing cognitive processes, making it challenging to dissociate the neural dynamics that support cognitive processes from those supporting related movements. In such cases, a critical issue is whether cognitive processes are separable from related movements, or if they are driven by common neural mechanisms. Here, we demonstrate how the separability of cognitive and motor processes can be assessed, and, when separable, how the neural dynamics associated with each component can be isolated. We establish a novel two-context behavioral task in mice that involves multiple cognitive processes and show that commonly observed dynamics taken to support cognitive processes are strongly contaminated by movements. When cognitive and motor components are isolated using a novel approach for subspace decomposition, we find that they exhibit distinct dynamical trajectories. Further, properly accounting for movement revealed that largely separate populations of cells encode cognitive and motor variables, in contrast to the mixed selectivity often reported. Accurately isolating the dynamics associated with particular cognitive and motor processes will be essential for developing conceptual and computational models of neural circuit function and evaluating the function of the cell types of which neural circuits are composed.

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bioRxiv2018

Visualization of axonal protein allocation in Drosophila with whole brain localization microscopy

Long-term memory (LTM) formation requires learning-induced protein synthesis in specific neurons and synapses within a neural circuit. Precisely how neural activity allocates new proteins to specific synaptic ensembles, however, remains unknown. We developed a deep-tissue super-resolution imaging tool suitable for single-molecule localization in intact adult Drosophila brain, and focused on the axonal protein allocation in mushroom body (MB), a central neuronal structure involved in olfactory memory formation. We found that insufficient training suppresses LTM formation by inducing the synthesis of vesicular monoamine transporter (VMAT) proteins within a dorsal paired medial (DPM) neuron, which innervates all axonal lobes of the MB. Surprisingly, using our localization microscopy, we found that these learning-induced proteins are distributed only in a subset of DPM axons in specific sectors along the MB lobes. This neural architecture suggests that sector-specific modulation of neural activity from MB neurons gates consolidation of early transient memory into LTM.

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bioRxiv2026

Adolescent blockade of complement signaling in the lateral septum increases social novelty seeking behavior in male mice

Social behaviors are critical for survival and change dramatically over the lifespan. Adolescence is a critical period of development during which social novelty seeking peaks before declining into adulthood. Adolescence is also a time of pronounced neural circuit refinement as excess synapses are eliminated. One critical mechanism supporting this maturation of neural circuits is microglial pruning of synapses through the classical complement signaling cascade. However, it remains unclear how microglial pruning of the neural circuitry supporting social novelty preference shapes the trajectory of this behavior during adolescence. To address this, we blocked microglial complement-dependent pruning during adolescence by injecting neutrophil inhibitory factor (NIF; blocks the adhesion of ligands to CD11b/C3 receptor) in the lateral septum (LS), a key node in the social circuitry supporting social novelty preference, in male mice. We found that NIF administration into the LS during adolescence increased preference for the novel social chamber over the familiar as compared to control PBS administration. LS-NIF treatment had no impact on anxiety-like behavior in the light-dark box test and no effect on sociability. LS-NIF treatment also decreased the expression of immune-related genes in the LS as compared to PBS treatment. These data support the hypothesis that complement-dependent microglial synaptic elimination in the LS is critical for the developmental progression of social novelty preference.

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bioRxiv2021

Passive clearing and 3D lightsheet imaging of the intact and injured spinal cord in mice

The spinal cord contains a diverse array of sensory and motor circuits that are essential for normal function. Spinal cord injury (SCI) permanently disrupts neural circuits through initial mechanical damage, as well as a cascade of secondary injury events that further expand the spinal cord lesion, resulting in permanent paralysis. Tissue clearing and 3D imaging have recently emerged as promising techniques to improve our understanding of the complex neural circuitry of the spinal cord and the changes that result from damage due to SCI. However, the application of this technology for studying the intact and injured spinal cord remains limited. Here we optimized the passive CLARITY technique (PACT) to obtain gentle and efficient clearing of the murine spinal cord without the need for specialized equipment. We demonstrate that PACT clearing enables 3D imaging of multiple fluorescent labels in the spinal cord to assess molecularly defined neuronal populations, acute inflammation, long-term tissue damage, and cell transplantation. Collectively, these procedures provide a framework for expanding the utility of tissue clearing to enhance the study of spinal cord neural circuits, as well as cellular- and tissue-level changes that occur following SCI.

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bioRxiv2026

A biointegrated living brain stimulator evokes specific neural signalling

Implanted brain stimulators play a crucial role in treating various neurological disorders, including Parkinsons disease (PD), Alzheimers disease, epilepsy, and depression. However, none of the existing implanted brain stimulators can realize specific neuromodulation due to fundamental disparities in signal transmission between electrical signal-induced neuronal responses and neurotransmitter-evoked neural signalling in natural neural circuits, leading to persistent challenges in biosafety and therapeutic effectiveness. Inspired by the dopaminergic neural circuit, we report a biointegrated living brain stimulator (BBS) that integrates ferroelectric bioelectronics, dopaminergic cells, and a gelatin hydrogel matrix, enabling dopamine neurotransmitter-evoked neural signalling. In contrast to conventional brain stimulators, the BBS are capable of programmed secretion of physiological-level dopamine, specifically activating nigral dopamine pathways and restoring motor function in a rodent PD model. By integrating the advantages of both bioelectronics and medicine, this lifelike BBS offers a great promise for next-generation bioelectronics, medicine, and brain-machine interfaces.

bioengineering↗

bioRxiv2024

3D Bioprinting of Human Neural Tissues with Functional Connectivity

Probing how the human neural networks operate is hindered by the lack of reliable human neural tissues amenable for dynamic functional assessment of neural circuits. We developed a 3D bioprinting platform to assemble tissues with defined human neural cell types in a desired dimension using a commercial bioprinter. The printed neuronal progenitors differentiate to neurons and form functional neural circuits in and between tissue layers with specificity within weeks, evidenced by the cortical-to-striatal projection, spontaneous synaptic currents and synaptic response to neuronal excitation. Printed astrocyte progenitors develop into mature astrocytes with elaborated processes and form functional neuron-astrocyte networks, indicated by calcium flux and glutamate uptake in response to neuronal excitation under physiological and pathological conditions. These designed human neural tissues will likely be useful for understanding the wiring of human neural networks, modeling pathological processes, and serving as platforms for drug testing.

bioengineering↗

bioRxiv2026

The membrane-tethered cis-ligand Belly roll elicits GPCR signaling thereby enabling adaptive avoidance behaviors

Animals adapt their behavioral responses to sensory stimuli through neuromodulatory circuits. Increasing fluid osmolality drives water-seeking behaviors via neuromodulation. However, the neural circuits and molecular mechanisms linking internal osmotic state to behavioral adaptation remain unclear. Here, we show that desiccation stress increases hemolymph osmolality and enhances avoidance of dry substrates in Drosophila larvae, enabling larvae to seek humid environments. We identify the abdominal leucokinin-producing (ABLK) neurons as a key circuit node that mediates this adaptive response. We further show that the GPI-anchored protein Belly roll (Bero), a member of the lymphocyte antigen-6/urokinase-type plasminogen activator receptor (LU) superfamily, acts as a non-canonical endogenous cis-ligand for the neuropeptide G protein-coupled receptor Allatostatin C receptor 2 (AstC-R2). Genetic, biochemical, and imaging analyses revealed that Bero activates AstC-R2 to induce phospholipase C {beta} (PLC{beta})-dependent signaling, thereby suppressing sensory transmission in ABLK neurons. Desiccation-induced increase in hemolymph osmolality activates VMA-AstC neurons to trigger Allatostatin C (AstC) release, which antagonizes Bero-mediated AstC-R2 signaling and promotes dry substrate avoidance. Together, our findings uncover a neural circuit and a molecular mechanism by which changes in internal physiological state dynamically switch GPCR signaling through the opposing actions of membrane-tethered and secreted ligands, thereby reshaping adaptive behavioral responses.

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bioRxiv2024

Regional heterogeneities of oligodendrocytes determine biased distribution pattern of Ranvier nodes along single axons in sound localization circuit

Spacing of Ranvier nodes along myelinated axons is a critical determinant of conduction velocity, influencing spike arrival timing and hence neural circuit function. In the chick brainstem auditory circuit, the pattern of nodal spacing varies regionally along single axons, enabling precise binaural integration for sound localization. Using this model, we investigated the potential factors underlying the biased nodal spacing pattern. 3D morphometry revealed that these axons were almost fully myelinated by oligodendrocytes exhibiting distinct morphologies and cell densities across regions after hearing onset. The structure of axons did not affect internodal length. Inhibiting vesicular release from the axons did not affect internodal length or oligodendrocyte morphology, but caused unmyelinated segments on the axons by suppressing oligodendrogenesis near the presynaptic terminals. These results suggest that the regional heterogeneity in the intrinsic properties of oligodendrocytes is a prominent determinant of the biased nodal spacing pattern in the sound localization circuit, while activity-dependent signaling supports the pattern by ensuring adequate oligodendrocyte density. Our findings highlight the importance of oligodendrocyte heterogeneity in fine-tuning neural circuit function.

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bioRxiv2025

Unfolding the Black Box of Recurrent Neural Networks for Path Integration

Path integration is essential for spatial navigation. Experimental studies have identified neural correlates for path integration, but exactly how the neural system accomplishes this computation remains unresolved. Here, we adopt recurrent neural networks (RNNs) trained to perform a path integration task to explore this issue. After training, we borrow neuroscience prior knowledge and methods to unfold the black box of the trained model, including: clarifying neuron types based on their receptive fields, dissecting information flows between neuron groups by pruning their connections, and analyzing internal dynamics of neuron groups using the attractor framework. Intriguingly, we uncover a hierarchical information processing pathway embedded in the RNN model, along which velocity information of an agent is first forwarded to band cells, band and grid cells then coordinate to carry out path integration, and finally grid cells output the agent location. Inspired by the RNN-based study, we construct a neural circuit model, in which band cells form one-dimensional (1D) continuous attractor neural networks (CANNs) and serve as upstream neurons to support downstream grid cells to carry out path integration in the 2D space. Our study challenges the conventional view of considering grid cells as the principal velocity integrator, and supports a neural circuit model with the hierarchy of band and grid cells.

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bioRxiv2019

Expecting social punishment facilitates control over a decision under uncertainty by recruiting medial prefrontal cortex

In many decision-making situations, uncertainty facilitates suboptimal choices. However, when individuals are in a socially dangerous situation such that wrong choice would lead to a social punishment such as blame of the supervisor, they might try to minimize suboptimal choices to avoid it. In this functional MRI study, 46 participants performed a choice task in which the probability of a correct choice with a given cue and the conditional probability of blame feedback (by making an incorrect choice) changed continuously. Using computational models of behavior, we found that participants optimized their decision by suppressing the decision noise induced by uncertainty. Simultaneously, expecting blame significantly deteriorated participants mood. Model-based fMRI analyses and dynamic causal modeling revealed that the optimization mechanism based on the expectation of being blamed was controlled by a neural circuit centered on right medial prefrontal cortex. These results show novel behavioral and neural mechanisms regarding how humans optimize uncertain decisions under the expectation of being blamed that negatively influences mood.\n\nSignificance StatementPeople occasionally encounter a situation that forces us to make an optimal decision under uncertainty, which is difficult, and a failure to make a good choice might be blamed by their supervisor. Although it might be hard to make right decision, they make more effort to make a good decision, which might help them to escape from the aversive outcome. However, such kind of stressful situation influences our mood to be negative. Using the computational modelling, we showed that participants computed how it is likely to be blamed and this computation motivated people to control uncertainty-induced decision noise by recruiting a neural circuit centered on the medial prefrontal cortex. However, an expectation of being blamed significantly deteriorated participants mood.

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