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bioRxiv2021

ICoRD: Iterative Correlation-Based ROI Detection Method for the Extraction of Neural Signals in Calcium Imaging

In vivo calcium imaging is a standard neuroimaging technique that allows selective observation of target neuronal activities. In calcium imaging, neuron activation signals provide key information for the investigation of neural circuits. For efficient extraction of the calcium signals of neurons, selective detection of the region of interest (ROI) pixels corresponding to the active subcellular region of the target neuron is essential. However, current ROI detection methods for calcium imaging data exhibit a relatively low signal extraction performance from neurons with a low signal-to-noise power ratio (SNR). This is problematic because a low SNR is unavoidable in many biological experiments. Therefore, we propose an iterative correlation-based ROI detection (ICoRD) method that robustly extracts the calcium signal of the target neuron from a calcium imaging series with severe noise. ICoRD extracts calcium signals closer to the ground-truth calcium signal than the conventional method from simulated calcium imaging data in all low SNR ranges. Additionally, this study confirmed that ICoRD robustly extracts activation signals against noise, even within in vivo environments. ICoRD showed reliable detection from neurons with a low SNR and sparse activation, which were not detected by conventional methods. ICoRD will facilitate our understanding of neural circuit activity by providing significantly improved ROI detection in noisy images.

neuroscience↗

bioRxiv2018

Specific octopaminergic neurons arbitrate between perseverance and reward in hungry Drosophila

In pursuit of palatable food, hungry animals mobilize significant energy resources and overcome obstacles, exhaustion and fear. Their perseverance depends on metabolic state, internal motivation and the expected benefit. Sustained commitment to a trying task is crucial, however, disengagement from one behavior to engage into another can be essential for optimal adaptation and survival. How neural circuits allow prioritizing perseverance over withdrawal based on the animals need is not understood. Using a single fly spherical treadmill, we show that hungry flies display increasing perseverance to track a food odor in the repeated absence of the predicted food reward. While this perseverance is mediated by a group of dopaminergic neurons, a subset of neurons expressing octopamine, the invertebrate counterpart of noradrenaline, provide reward feedback and counteract dopamine-motivated food seeking. Our data and modeling suggest that two important neuromodulators tally internal and external signals to coordinate motivation-dependent antagonistic behavioral drives: perseverance vs. change of behavior.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC=\"FIGDIR/small/259119_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (21K):\norg.highwire.dtl.DTLVardef@9833e1org.highwire.dtl.DTLVardef@7616d4org.highwire.dtl.DTLVardef@d4e8bforg.highwire.dtl.DTLVardef@1fc615c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LILack of reward stimulates perseverance, and not quitting.\nC_LIO_LIDopaminergic neurons previously implicated in aversive learning promote perseverance.\nC_LIO_LISugar responsive octopaminergic neurons directly counteract perseverant odor tracking through a downstream inhibitory neuron.\nC_LIO_LIComputational modeling supports a simple neural circuit featuring antagonistic functions for dopamine and octopamine as tallies of expense and gain.\nC_LI

neuroscience↗

bioRxiv2021

Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures

Astrocytes are dynamic cells with important roles in brain function and neurological disease. There are notable species differences between human astrocytes and commonly used animal models. However, changes of the molecular attributes of human astrocytes across disease states, sex, and age are largely unknown, which is a barrier in understanding human astrocyte biology and its potential involvement in neurological diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. Here, we identified a robust transcriptomic signature of human astrocytes in the tumor-surrounding microenvironment, including upregulation of proliferation processes, along with downregulation of genes involved in ionic homeostasis and synaptic function, suggesting involvement of peri-tumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of astrocyte reactivity, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified some of the first transcriptomic evidence of sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurological disorders. Overall, genes involved in synaptic function exhibited dynamic changes in multiple conditions. This data provides powerful new insights into human astrocyte biology in several biologically relevant states, that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans. Significance StatementAstrocytes are an abundant class of cells playing integral roles in the central nervous system. Astrocyte dysfunction is implicated in a variety of human neurological diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found changes suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction, aging-associated decline in astrocyte-synapse interactions, ionic transport changes with brain maturation, and some of the first evidence of sexual dimorphism in human astrocytes. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.

neuroscience↗

bioRxiv2022

Glia-mediated cerebellar pain modulation

Clinical studies have revealed that the cerebellum is activated by noxious stimuli or pathological pain, and its removal results in somatosensory dysfunction. However, the neural circuits and molecular mechanisms underlying the processing of noxious information in the cerebellum remain unknown. Using two-photon microscopy and optogenetics in mice, we found that the locus coeruleus (LC) terminals in the cerebellar cortex release noradrenaline (NA) in response to cutaneous noxious electrical stimuli. Most Bergmann glia (BG) accumulated this LC-NA noxious information by increasing intracellular calcium in an integrative manner. This global calcium activation of BG, referred to as "flare," was also elicited in response to an intraplantar capsaicin injection. Chemogenetic inactivation of LC terminals or BG in the cerebellar cortex suppressed BG flares and reduced licking, a nocifensive behavior associated with capsaicin-induced pain. BG-specific knockdown of -1 adrenergic receptors also suppressed capsaicin-induced BG flares and licking. Chemogenetic activation of BG or an intraplantar capsaicin injection reduced Purkinje cell firings, which disinhibited the output activity of the deep cerebellar nuclei. These results suggest that BG in the cerebellar cortex play an essential role in computing noxious information ascending from the LC and modulate pain-related behaviors by controlling the activity of the cerebellar neural circuits. One Sentence SummaryBergmann glia mediate noxious information processing in the cerebellum

neuroscience↗

bioRxiv2021

Relating spinal injury-induced neuropathic pain and spontaneous afferent activity to sleep and respiratory dysfunction

Spinal cord injury (SCI) can induce dysfunction in a multitude of neural circuits including those that lead to impaired sleep, respiratory dysfunction and neuropathic pain. We used a lower thoracic rodent contusion SCI model - known to develop mechanosensory stimulus hypersensitivity, and spontaneous activity in primary afferents that associates neuropathic pain - and paired this with new approaches that enabled chronic capture of three state sleep and respiration to characterize dysfunction and assess possible interrelations. Noncontact electric field sensors were embedded into home cages for noninvasive capture in naturally behaving mice of the temporal evolution of sleep and respiration changes for 6 weeks after SCI. Hindlimb mechanosensitivity was assessed weekly, and terminal experiments measured primary afferent spontaneous activity in situ from intact lumbar dorsal root ganglia (DRG). We observed that SCI led to increased spontaneous primary afferent activity (both firing rate and the number of spontaneously active DRGs) that correlated with reduced hindpaw mechanical sensitivity, increased respiratory rate variability, and increased sleep fragmentation. This is the first study to measure and link sleep dysfunction and variability in respiratory rate in a SCI model of neuropathic pain, and thereby provide broader insight into the magnitude of overall stress burden initiated by neural circuit dysfunction after SCI.

neuroscience↗

bioRxiv2026

Cannabidiol (CBD) Promotes Post-TBI Astrocyte Viability and Decreases Injury-Induced Glial Stress Responses Across Zebra Finch Song Control Nuclei

The non-euphorigenic phytocannabinoid cannabidiol (CBD) has demonstrated therapeutic efficacy in childhood-onset epilepsies. Using a songbird preclinical model we have found that CBD promotes recovery of learned vocalizations following focal motor cortical injury. But questions about cellular mechanisms supporting this protection remained. Songbird vocal learning, like human speech, depends on development and maintenance of specialized neural circuits. Partial lesioning (microlesions) of the vocal pre-motor cortical-like song region HVC transiently disrupts song structure and triggers injury-associated cellular stress responses across interconnected song regions. Building on prior findings that CBD reduces neuroinflammation and synaptic loss in zebra finch song circuitry, we investigated potential astrocyte contributions. Here we report that HVC microlesions induce significant cell loss in HVC and its projection targets (vocal motor RA and striatal Area X), with a substantial fraction of apoptotic cells being astrocytes. CBD treatment reduces lesion-induced apoptosis and preserves astrocyte populations, indicating enhanced astrocyte viability as a major factor in CBD-mediated neuroprotection. Microlesions also elevate astrocyte stress, including increased lysosomal burden (LAMP1/LC3 expression) and astrocytic reactivity markers (C3, S100A10, aromatase). CBD attenuates these stress responses while enhancing neuroprotective metabolic and antioxidant mediators (glutamine synthetase [GS], glutamate-cysteine ligase modifier subunit [GCLM]), consistent with improved antioxidant and excitotoxicity resistance. Given that development-dependent sensorimotor skills (e.g. song in songbirds, language and many others in humans) depend on sensitive period establishment and ongoing post-learning maintenance of specialized neural circuits vulnerable to traumatic disruption, the zebra finch model provides a valuable preclinical platform for investigating glial-targeted interventions to promote circuit resilience and functional recovery after TBI.

pharmacology and toxicology↗

bioRxiv2018

Noninvasive Vagus Nerve Stimulation Alters Neural Response and Physiological Autonomic Tone to Noxious Thermal Challenge

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n=15 sham and n=15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group x time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group x time x GSR analysis showed a significantly decreased response in nVNS group (p < .0005) in bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output.

neuroscience↗

bioRxiv2020

Plasticity in visual cortex is disrupted in a mouse model of tauopathy and neurodegeneration

Neurodegeneration is a hallmark of many dementias and is thought to underlie a progressive impairment of neural plasticity. How neurodegeneration affects plasticity in neural circuits is not known. We therefore characterised the impact of tau-driven neurodegeneration on plasticity in the visual system, where normal function is well understood. We studied a very simple form of visual plasticity that allowed us to track both long timescales (across days) and shorter timescales (over minutes). We recorded the local field potential in the primary visual cortex of rTg4510 transgenic mice, a mouse model of tauopathy, while animals were repeatedly exposed to the same stimulus over the course of 9 days. We studied animals at early stages of neurodegeneration (5 months old) and at a more advanced stage where pathology is evident (8 months). We found that both short- and long-term visual plasticity were already disrupted at early stages of neurodegeneration, and were further reduced in older animals, such that it was abolished in mice expressing the mutant tau. Additionally, we found that visually evoked behaviours were disrupted in both younger and older mice expressing the mutant tau. Our results show that visual cortical plasticity and visually evoked behaviours are disrupted in the rTg4510 model of tauopathy, even at early stages of neurodegeneration. This simple measure of neural plasticity may help understand how neurodegeneration disrupts neural circuits, and offers a translatable platform for detection and tracking of the disease. HighlightsO_LIVisual plasticity is disrupted at early stages of neurodegeneration in rTg4510 mice C_LIO_LIVisual plasticity is reduced in older animals, particularly during neurodegeneration C_LIO_LIInstinctive visual behaviours are reduced in neurodegeneration C_LIO_LIShort-term visual plasticity is reduced in neurodegeneration C_LI

neuroscience↗

bioRxiv2026

Multidimensional control of ingestive behavior by lateral hypothalamic neurotensin neurons

Consumption of food and water is regulated by interactions between neural circuits that govern motivational drive states, arousal, motor activity, and reward signaling, among other factors. Neurons in the lateral hypothalamus that express the neuropeptide neurotensin (LH-Nts neurons) are known to influence many of these elements, but their precise role in regulating specific aspects of ingestive behavior remains unclear. Utilizing a tightly controlled head-fixed task, we find that LH-Nts neurons strongly encode the rate of licking for water and sweet solutions, with weaker modulation of activity by solution identity and restriction state. Silencing LH-Nts neurons reduces water intake but has little direct effect on hunger or satiety. Instead, we find that these neurons impact multiple underlying behavioral components necessary for food consumption, including arousal and engagement with a novel food source, and also influence thermoregulation and metabolism. Together, these data establish tonic activity of LH-Nts neurons as a critical signal supporting exploration and volitional movement, while also delineating a role for these neurons in driving active consumption, particularly of water. Furthermore, quantitative projection mapping revealed widespread innervation of structures linked to thirst, arousal, reward, metabolism, and facial motor control, suggesting that these neurons play an important role coordinating neural circuits governing multiple different aspects of ingestion.

neuroscience↗

bioRxiv2020

Behavioral evidence for nested central pattern generator control of Drosophila grooming

Central pattern generators (CPGs) are neurons or neural circuits that produce periodic output without requiring patterned input. More complex behaviors can be assembled from simpler subroutines, and nested CPGs have been proposed to coordinate their repetitive elements, organizing control over different time-scales. Here, we use behavioral experiments to establish that Drosophila grooming may be controlled by nested CPGs. On a short time-scale (5-7 Hz), flies execute periodic leg sweeps and rubs. More surprisingly, transitions between bouts of head cleaning and leg rubbing are also periodic on a longer time-scale (0.3 - 0.6 Hz). We examine grooming at a range of temperatures to show that the frequencies of both oscillations increase - a hallmark of CPG control - and also that the two time-scales increase at the same rate, indicating that the nested CPGs may be linked. This relationship also holds when sensory drive is held constant using optogenetic activation, but the rhythms can decouple in spontaneously grooming flies, showing that alternative control modes are possible. Loss of sensory feedback does not disrupt periodicity but slows the longer time-scale alternation. Nested CPGs simplify generation of complex but repetitive behaviors, and identifying them in Drosophila grooming presents an opportunity to map the neural circuits that constitute them.

neuroscience↗

bioRxiv2026

Functional Cell-Type Identification in Neuronal Networks Using High-Density Microelectrode Arrays

The reliable identification of neuronal cell types - in particular, the distinction of excitatory (E) and inhibitory (I) neurons on the basis of extracellular recordings without post-hoc immunostaining or genetic labeling - remains a key challenge in neural-circuit analysis. High-density microelectrode arrays (HD-MEAs) have emerged as a powerful tool to address this issue, enabling simultaneous single-cell and network-level electrophysiology. Here, we present two complementary strategies for establishing cell-type ground truth based on HD-MEA recordings: (i) chemogenetic interneuron activation to label putative inhibitory neurons according to their functional response, and (ii) controlled mixing of excitatory and inhibitory hiPSC-derived populations at defined ratios. A classifier combining action potential waveform morphology and autocorrelogram-based discharge dynamics achieves robust cell-type discrimination in in vitro recordings of rat primary cortical cultures and hiPSC-derived networks, as well as in in vivo recordings of rat and mouse - i.e., across several species, recording modalities, and preparation types. Applied to unlabeled data, the classifier reveals cell-type-specific network dynamics during bursts, including an inhibition activity signature preceding burst onsets. Leveraging the HD-MEA spatiotemporal resolution, label-free electrophysiological footprint reconstruction enables a morphological characterization of putative E and I neurons without post-hoc staining. The classification pipeline represents a scalable framework for functional cell-type phenotyping with broad relevance for precision neural-circuit analysis and disease modeling.

neuroscience↗

bioRxiv2024

Adjacent Neuronal Fascicle Guides Motoneuron 24 Dendritic Branching and Axonal Routing Decisions through Dscam1 Signaling

The formation and precise positioning of axons and dendrites are crucial for the development of neural circuits. Although juxtracrine signaling via cell-cell contact is known to influence these processes, the specific structures and mechanisms regulating neuronal process positioning within the central nervous system (CNS) remain to be fully identified. Our study investigates motoneuron 24 (MN24) in the Drosophila embryonic CNS, which is characterized by a complex yet stereotyped axon projection pattern, known as axonal routing. In this motoneuron, the primary dendritic branches project laterally toward the midline, specifically emerging at the sites where axons turn. We observed that Scp2-positive neurons contribute to the lateral fascicle structure in the ventral nerve cord (VNC) near MN24 dendrites. Notably, the knockout of the Down syndrome cell adhesion molecule (dscam1) results in the loss of dendrites and disruption of proper axonal routing in MN24, while not affecting the formation of the fascicle structure. Through cell-type specific knockdown and rescue experiments of dscam1, we have determined that the interaction between MN24 and Scp2-positive fascicle, mediated by Dscam1, promotes the development of both dendrites and axonal routing. Our findings demonstrate that the holistic configuration of neuronal structures, such as axons and dendrites, within single motoneurons can be governed by local contact with the adjacent neuron fascicle, a novel reference structure for neural circuitry wiring. Significance SummaryWe uncover a key neuronal structure serving as a guiding reference for neural circuitry within the Drosophila embryonic CNS, highlighting the essential role of an adjacent axonal fascicle in precisely coordinating axon and dendrite positioning in motoneuron 24 (MN24). Our investigation of cell-cell interactions between motoneurons and adjacent axonal fascicles-- crucial for initiating dendrite formation, soma migration, and axonal pathfinding in MN24-- emphasizes the neuronal fascicles significance in neural circuit formation through Dscam1-mediated inter-neuronal communication. This enhances our understanding of the molecular underpinnings of motoneuron morphogenesis in Drosophila. Given the occurrence of analogous axon fascicle formations within the vertebrate spinal cord, such structures may play a conserved role in the morphogenesis of motoneurons via Dscam1 across phyla.

neuroscience↗

bioRxiv2024

Recent odor experience selectively modulates olfactory sensitivity across the glomerular output in the mouse olfactory bulb

Although animals can reliably locate and recognize odorants embedded in complex environments, the neural circuits for accomplishing these tasks remain incompletely understood. Adaptation is likely to be important as it could allow neurons in a brain area to adjust to the broader sensory environment. Adaptive processes must be flexible enough to allow the brain to make dynamic adjustments, while maintaining sufficient stability so that organisms do not forget important olfactory associations. Processing within the mouse olfactory bulb is likely involved in generating adaptation, although there are conflicting models of how it transforms the glomerular output of the mouse olfactory bulb. Here we performed 2-photon Ca2+ imaging from mitral/tufted glomeruli in awake mice to determine the time course of recovery from adaptation, and whether it acts broadly or selectively across the glomerular population. Individual glomerular responses, as well as the overall population odor representation was similar across imaging sessions. However, odor-concentration pairings presented with interstimulus intervals upwards of 30-s evoked heterogeneous adaptation that was concentration-dependent. We demonstrate that this form of adaptation is unrelated to variations in respiration, and olfactory receptor neuron glomerular measurements indicate that it is unlikely to be inherited from the periphery. Our results indicate that the olfactory bulb output can reliably transmit stable odor representations, but recent odor experiences can selectively shape neural responsiveness for upwards of 30 seconds. We propose that neural circuits that allow for non-uniform adaptation across mitral/tufted glomerular could be important for making dynamic adjustments in complex odor environments.

neuroscience↗

bioRxiv2026

Netrin signaling shapes sexually dimorphic neurite branching of a sex-shared interneuron in C. elegans

Sexually dimorphic behaviors arise from underlying differences in neural circuit architecture between the sexes, yet the molecular mechanisms that establish these structural differences remain poorly understood. In Caenorhabditis elegans, the sex-shared interneuron AVG exhibits sexually dimorphic synaptic connectivity, offering a model for investigating the development of sexually dimorphic neuronal morphology. Here, we identified that AVG displays male-specific neurite branching and demonstrated that the conserved axon guidance cue UNC-6/Netrin and its receptor UNC-40/DCC are essential for this structural remodeling. Cell-specific manipulation of sexual identity revealed that male identity confers branching competence to AVG. Loss of UNC-6 or UNC-40 abolished branch formation, whereas loss of the alternate Netrin receptor UNC-5/Unc5 had no detectable effect. Cell-specific rescue experiments showed that UNC-40 functions in AVG through its UNC-6 binding domains. Furthermore, genetic ablation of the male-specific presynaptic neuron PCA, which expresses unc-6, diminished AVG branch length, establishing PCA as a candidate local source of UNC-6. Together, our findings support a model in which presynaptic UNC-6/Netrin cues from male-specific neurons promote dimorphic neurite branching in sex-shared neurons, illustrating how evolutionarily conserved signaling molecules are redeployed during sexual maturation to sculpt sex-specific neural circuits.

neuroscience↗

bioRxiv2022

Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons

The formation of neural circuits requires extensive interactions of cell-surface proteins to guide axons to their correct target neurons. Trans-cellular interactions of the adhesion G protein-coupled receptor latrophilin-2 (Lphn2) with its partner teneurin-3 instruct the precise assembly of hippocampal networks by reciprocal repulsion. Lphn2 acts as a receptor in distal CA1 neurons to direct their axons to proximal subiculum, and as a repulsive ligand in proximal subiculum to direct proximal CA1 axons to distal subiculum. It remains unclear if Lphn2-mediated intracellular signaling is required for its role in either context. Here, we show that Lphn2 couples to G12/13 in heterologous cells, which is increased by constitutive exposure of the tethered agonist. Specific mutations of Lphn2s tethered agonist region disrupt its G protein coupling and autoproteolytic cleavage, whereas mutating the autoproteolytic cleavage site prevents cleavage but preserves a functional tethered agonist. Using an in vivo misexpression assay, we demonstrate that wild-type Lphn2 misdirects proximal CA1 axons to proximal subiculum and that Lphn2 tethered agonist activity is required for its role as a repulsive receptor. By contrast, neither tethered agonist activity nor autoproteolysis was necessary for Lphn2s role as a repulsive ligand. Thus, tethered agonist activity is required for Lphn2-mediated neural circuit assembly in a context-dependent manner.

developmental biology↗

bioRxiv2025

Functional Role for Cas Cytoplasmic Adaptor Proteins During Cortical Axon Pathfinding

Proper neural circuit organization requires individual neurons to project to their targets with high specificity. While several guidance molecules have been shown to mediate axonal fasciculation and pathfinding, less is understood about how neurons intracellularly interpret and integrate these cues. Here we provide genetic evidence that the Crk-Associated Substrate (Cas) family of intracellular adaptor proteins is required for proper fasciculation and guidance of two cortical white matter tracts: the Anterior Commissure (AC) and thalamocortical axons (TCAs). Using a Cas Triple Conditional Knock Out (Cas TcKO) mouse model, we show that Cas proteins are required for proper TCA projection by a non-neuronal cortical cell population. We also demonstrate a requirement of the {beta}1-integrin receptor for TCA projection, similarly in a population of non-neuronal cortical cells. Additional analysis of Cas TcKO mutants reveals a role for Cas proteins in AC fasciculation, here within the neurons themselves. This AC fasciculation requirement is not phenocopied in {beta}1-integrin deficient mutants, suggesting that Cas proteins might signal downstream of a different receptor during this axon pathfinding event. These findings implicate Cas proteins as key mediators of cortical axon tract fasciculation and guidance. Author SummaryIn the developing nervous system, neurons extend axons--long projections that relay information to their targets--to establish neural circuits. Axons follow specific pathways directed by extracellular guidance cues, much like street signs direct traffic. While these guidance cues are well studied, how neurons internally interpret and respond to these signals remains unclear. Here, we examine the role of the Crk-Associated Substrate (Cas) family of intracellular adaptor proteins in axon guidance within cortical axon tracts. Using genetic techniques to selectively remove Cas gene function from specific cell types, we demonstrate that Cas proteins are required for proper fasciculation (bundling) of anterior commissure axons, acting directly within the projecting axons themselves. Additionally, Cas proteins are required for proper guidance of thalamocortical projections--axons connecting the thalamus with the cortex. However, in this case, Cas proteins do not act within projecting axons but instead direct target neurons to their final positions. We further show that the {beta}1-integrin receptor is similarly required for thalamocortical axon projection. These findings provide genetic evidence for a critical role of Cas adaptor proteins in both fasciculation and guidance of cortical axon tracts.

neuroscience↗

bioRxiv2025

Coincidence detection supported by electrical synapses is shaped by the D-type K+ current

Electrical synapses mediated by gap junctions are widespread in the mammalian brain, playing essential roles in neural circuit function. Beyond their role synchronizing neuronal activity, they also support complex computations such as coincidence detection--a circuit mechanism in which differences in input timing are encoded by the firing rates of coupled neurons, enabling preferential responses to synchronous over temporally dispersed inputs. Electrical coupling allows each neuron to act as a current sink for its partner during independent depolarizations, thereby reducing excitability. In contrast, synchronous inputs across the network minimize voltage differences through gap junctions, reducing current shunting and increasing spiking probability. However, the contribution of intrinsic neuronal properties to coincidence detection remains poorly understood. Here, we investigated this issue in the Mesencephalic Trigeminal (MesV) Nucleus of mice, a structure composed of somatically-coupled neurons. Using whole-cell recordings and pharmacological tools, we examined the role of the D-type K+ current (ID), finding that it critically shapes both the intrinsic electrophysiological properties of MesV neurons and the dynamics of electrical synaptic transmission. Its fast activation kinetics and subthreshold voltage range of activation make ID a key determinant of transmission strength and timing. Furthermore, the ID, likely mediated by Kv1 subunits, is expressed at the soma and the axon initial segment. Finally, we characterized two key parameters of coincidence detection--precision (time window for effective input summation) and gain (differential response to coincident versus dispersed inputs)--finding that ID enhances precision by accelerating membrane repolarization and reduces the gain by limiting neuronal excitability. SUMMARYElectrical synapses enable neural circuits to perform as coincidence detectors, that is, to preferentially respond to simultaneous inputs. The temporal precision of this operation is critically determined by voltage-dependent conductances of the soma and proximal axon.

neuroscience↗

bioRxiv2021

AI-driven high-throughput automation of behavioral analysis and dual-channel wireless optogenetics for multiplexing brain dynamics

Advances in behavioral optogenetics are limited by the absence of high-throughput pipelines for the automated analysis of behavior in freely behaving animals. Although a variety of AI algorithms has been proposed that enable automation of behavioral analysis, existing methods are generally low-throughput. In addition, optogenetic manipulation of neural circuits typically requires physical tethers to light sources, which limits the number of brain areas that can be targeted and thus constrains behavioral testing. Here, we develop a new wireless platform that combines a battery-free dual-channel optogenetic implant with an AI algorithm for high-throughput behavioral analysis. In our platform, a customized AI algorithm detected and quantified freezing behavior of rats that had undergone fear conditioning. Notably, our platform allows up to four enclosures to be monitored simultaneously. Wireless dual-channel optogenetic devices were implanted in the basolateral amygdala (BLA) to permit independent modulation of BLA principal neurons (red light, AAV-CaMKII-JAWS) or BLA interneurons (blue light, AAV-mDlx-ChR2) in freely behaving animals. In vivo validation with behaving rats demonstrates the utility of the telemetry system for large-scale optogenetic studies. SignificanceAI algorithms can enable automation of behavioral analysis and thereby facilitate the progress on behavioral optogenetics. Successful integration of advanced wireless dual-channel optoelectronic devices with biological systems can also yield new tools and techniques for neuroscience research, particularly in the context of techniques for optogenetics. Here, we propose a new approach that combines an advanced AI algorithm with a low power wireless telemetry system, yielding powerful capabilities in the understanding of brain functions and the evaluation of the behavioral consequences of neural circuit manipulations. In vivo studies using optimized systems demonstrate high-throughput automation of behavioral manipulation and analysis via AI-powered wireless telemetry.

neuroscience↗