SEARCH · Search bioRxiv

Results for “neural circuits”

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 271 records · Page 15Linked to original sources

bioRxiv2026

When can neuronal activity-dependent homeostatic plasticity maintain circuit-level properties?

Neural circuits are remarkably robust to perturbations that threaten their function. Activity-dependent homeostatic plasticity (ADHP) is a stabilizing mechanism that supports robustness by tuning neuronal ion conductances to combat chronic over- or under-activity. Its restorative capacity has been demonstrated in the pyloric circuit of the crustacean stomatogastric ganglion, whose neurons must burst in a specific order to coordinate digestive muscles. After disruption by physical and pharmacological manipulations, this circuit reliably recovers not only the activity levels of constituent neurons, but also the proper burst order. But how could ADHP, operating only on local information about each neurons average activity, maintain higher-order circuit properties? We explored this question in a computational model of the pyloric pattern generator. We first optimized a set of pyloric-like networks, then optimized ADHP mechanisms for each network to restore its pyloric character after parametric perturbations. This was possible for some networks and impossible for others, so we aimed to explain this disparity. We found that successful homeostatic regulators target average neural activity levels which happen to occur only among pyloric circuits and not among non-pyloric ones, within the set of reachable circuit configurations. Therefore, in subsets of parameter space where such dissociation is possible, activity carries indirect information about burst order, which ADHP can exploit to maintain pyloricness. Other subsets, whose pyloric averages are inseparable from non-pyloric ones, cannot be perfectly regulated. This separability property may explain differences in recovery capacity across perturbations and across individuals.

neuroscience↗

bioRxiv2022

A connectomics-based taxonomy of mammals

Mammalian taxonomies are conventionally defined by morphological traits and genetics. How species differ in terms of neural circuits and whether inter-species differences in neural circuit organization conform to these taxonomies is unknown. The main obstacle for the comparison of neural architectures have been differences in network reconstruction techniques, yielding species-specific connectomes that are not directly comparable to one another. Here we comprehensively chart connectome organization across the mammalian phylogenetic spectrum using a common reconstruction protocol. We analyze the mammalian MRI (MaMI) data set, a database that encompasses high-resolution ex vivo structural and diffusion magnetic resonance imaging (MRI) scans of 124 species across 12 taxonomic orders and 5 superorders, collected using a single protocol on a single scanner. We assess similarity between species connectomes using two methods: similarity of Laplacian eigenspectra and similarity of multiscale topological features. We find greater inter-species similarities among species within the same taxonomic order, suggesting the connectome organization recapitulates traditional taxonomies defined by morphology and genetics. While all connectomes retain hallmark global features and relative proportions of connection classes, inter-species variation is driven by local regional connectivity profiles. By encoding connectomes into a common frame of reference, these findings establish a foundation for investigating how neural circuits change over phylogeny, forging a link from genes to circuits to behaviour.

neuroscience↗

bioRxiv2021

Distributed processing for action control by prelimbic circuits targeting anterior-posterior dorsal striatal subregions.

Fronto-striatal circuits have been extensively implicated in the cognitive control of behavioral output for both social and appetitive rewards. The functional diversity of prefrontal cortical populations is strongly dependent on their synaptic targets, with control of motor output strongly mediated by connectivity to the dorsal striatum. Despite evidence for functional diversity along the anterior-posterior axis of the dorsomedial striatum (DMS), it is unclear how distinct fronto- striatal sub-circuits support neural computations essential for action selection. Here we identify prefrontal populations targeting distinct DMS subregions and characterize their functional roles. We first performed neural circuit tracing to reveal segregated prefrontal populations defined by anterior/posterior dorsomedial striatal target. We then probed the functional relevance of these parallel circuits via in vivo calcium imaging and temporally precise causal manipulations during a feedback-based 2-alternative choice task. Single-photon imaging revealed circuit-specific representations of task-relevant information with prelimbic neurons targeting anterior DMS (PL::A- DMS) uniquely encoded choices and responses to negative outcomes, while prelimbic neurons targeting posterior DMS (PL::P-DMS) encoded internal representations of value and positive outcomes contingent on prior choice. Consistent with this distributed coding, optogenetic inhibition of PL::A-DMS circuits strongly impacted choice monitoring and behavioral control in response to negative outcomes while perturbation of PL::P-DMS signals impaired task engagement and strategies following positive outcomes. Di-synaptic retrograde tracing uncovered differences in afferent connectivity that may underlie these pathways functional divergence. Together our data uncover novel PL populations engaged in distributed processing for action control. SUMMARYO_LIPrelimbic cortex engages A- and P-DMS via distinct circuits C_LIO_LIPL::A-DMS and PL::P-DMS pathways encode divergent aspects of a simple goal-directed task C_LIO_LIPL::A-DMS pathways shape responding to negative outcomes via multiple mechanisms C_LIO_LIPL::P-DMS pathways guide engagement and choices in response to positive outcomes C_LIO_LIAfferent connectomes of PL neurons defined by A-P DMS target are distinct C_LI

neuroscience↗

bioRxiv2022

Two-photon patterned photostimulation with low-power, high-efficiency and reliable single-cell optogenetic control

Two-photon optogenetics enables selectively stimulating individual cells for manipulating neuronal ensembles. As the general photostimulation strategy, the patterned two-photon excitation has enabled millisecond-timescale activation for single or multiple neurons, but its activation efficiency is suffered from high laser power due to low beam-modulation efficiency. Here, we develop a high- efficiency beam-shaping method based on the Gerchberg-Saxton (GS) algorithm with spherical-distribution initial phase (GSSIP) to reduce the patterned two-photon excitation speckles and intensity. It can well control the phase of shaped beams to attain speckle-free accurate patterned illumination with an improvement of 44.21% in the modulation efficiency compared with that of the traditional GS algorithm. A combination of temporal focusing and the GSSIP algorithm (TF-GSSIP) achieves patterned focusing through 500-m-thickness mouse brain slices, which is 2.5 times deeper than the penetration depth of TF-GS with the same signal-to-noise ratio (SNR). With our method, the laser power can be reduced to only 55.56% of that with traditional method (the temporal focusing with GS, TF-GS) to reliably evoke GCaMP6s response in C1V1-expressing cultured neurons with single-cell resolution. Besides, the photostimulation efficiency is remarkably increased by 80.19% at the same excitation density of 0.27 mW/m2. This two-photon stimulation method with low-power, reliable and patterned illumination may pave the way for analyzing neural circuits and neural coding and decoding mechanism.

neuroscience↗

bioRxiv2026

Signatures of Hebbian plasticity in the nanoscale morphodynamics of cortical spines

The size, shape, and nanoscale organization of synaptic spines are predictive of physiological synaptic strength and thus key to connectome-based neural circuit models. In the intact brain, spine size and shape undergo continuous morphological remodeling. While these nanoscale morphodynamics are not well understood, it is clear that morphological changes that strongly impact synaptic strength should modify spine head and neck in a coordinated manner and that such coordinated remodeling can be triggered by spike-timing-dependent synaptic plasticity. Here we demonstrate unambiguous signatures of such coordinated spine remodeling from in vivo long-term nanoscopy of cortical spines. We infer data-driven generative models of synaptic spine morphodynamics. These models imply that although coordinated remodeling represents the smallest component of ongoing morphodynamic fluctuations, this component causes massive fluctuations in instantaneous synaptic strength. Despite these fluctuations, synaptic strengths exhibit a synapse-specific long-term persistent component that results from spine fluctuations exploring only a limited subregion of accessible spine morphospace. Our results suggest that nanoscale morphodynamic spine remodeling injects substantial fluctuations of instantaneous synaptic strength into the operation of cortical circuits. Connectome-based neural circuit models thus need to consider features of spine organization beyond spine head size and should be augmented by data-driven generative models of spine morphodynamics.

neuroscience↗

bioRxiv2021

Mapping circuit dynamics during function and dysfunction

Neural circuits can generate many spike patterns, but only some are functional. The study of how circuits generate and maintain functional dynamics is hindered by a poverty of description of circuit dynamics across functional and dysfunctional states. For example, although the regular oscillation of a central pattern generator is well characterized by its frequency and the phase relationships between its neurons, these metrics are ineffective descriptors of the irregular and aperiodic dynamics that circuits can generate under perturbation or in disease states. By recording the circuit dynamics of the well-studied pyloric circuit in C. borealis, we used statistical features of spike times from neurons in the circuit to visualize the spike patterns generated by this circuit under a variety of conditions. This unsupervised approach captures both the variability of functional rhythms and the diversity of atypical dynamics in a single map. Clusters in the map identify qualitatively different spike patterns hinting at different dynamical states in the circuit. State probability and the statistics of the transitions between states varied with environmental perturbations, removal of descending neuromodulation, and the addition of exogenous neuromodulators. This analysis reveals strong mechanistically interpretable links between complex changes in the collective behavior of a neural circuit and specific experimental manipulations, and can constrain hypotheses of how circuits generate functional dynamics despite variability in circuit architecture and environmental perturbations.

neuroscience↗

bioRxiv2024

Evolution of a central dopamine circuit underlies adaptation of light-evoked sensorimotor response in the blind cavefish, Astyanax mexicanus.

Adaptive behaviors emerge in novel environments through functional changes in neural circuits. While relationships between circuit function and behavior have been well studied, how evolution shapes those circuits and leads to behavioral adpation is poorly understood. The Mexican cavefish, Astyanax mexicanus, provides a unique genetically amendable model system, equipped with above ground eyed surface fish and multiple evolutionarily divergent populations of blind cavefish that have evolved in complete darkness. These differences in environment and vision provide an opprotunity to examine how a neural circuit is functionally influenced by the presence of light. Here, we examine differences in the detection, and behavioral response induced by non visual light reception. Both populations exhibit photokinetic behavior, with surface fish becoming hyperactive following sudden darkness and cavefish becoming hyperactive following sudden illumination. To define these photokinetic neural circuits, we integrated whole brain functional imaging with our Astyanax brain atlas for surface and cavefish responding to light changes. We identified the caudal posterior tuberculum as the central modulator for both light or dark stimulated photokinesis. To unconver how spatiotemporal neuronal activity differed between surface fish and cavefish, we used stable pan-neuronal GCaMP Astyanax transgenics to show that a subpopulation of darkness sensitve neurons in surface fish are now light senstive in cavefish. Further functional analysis revealed that this integrative switch is dependent on dopmane signaling, suggesting a key role for dopamine and a highly conserved dopamine circuit in modulating the evolution of a circuit driving an essential behavior. Together, these data shed light into how neural circuits evolved to adapte to novel settings, and reveal the power of Astyanax as a model to elucidate mechanistic ingiths underlying sensory adaptation. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/605141v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@145efeforg.highwire.dtl.DTLVardef@8b41e6org.highwire.dtl.DTLVardef@936979org.highwire.dtl.DTLVardef@1f18c5b_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗

bioRxiv2020

Extreme stiffness of neuronal synapses and implications for synaptic adhesion and plasticity

Synapses play a critical role in neural circuits, and they are potential sites for learning and memory. Maintenance of synaptic adhesion is critical for neural circuit function, however, biophysical mechanisms that help maintain synaptic adhesion are not clear. Studies with various cell types demonstrated the important role of stiffness in cellular adhesions. Although synaptic stiffness could also play a role in synaptic adhesion, stiffnesses of synapses are difficult to characterize due to their small size and challenges in verifying synapse identity and function. To address these challenges, we have developed an experimental platform that combines atomic force microscopy, fluorescence microscopy, and transmission electron microscopy. Here, using this platform, we report that functional, mature, excitatory synapses had an average elastic modulus of approximately 200 kPa, two orders of magnitude larger than that of the brain tissue, suggesting stiffness might have a role in synapse function. Similar to various functional and anatomical features of neural circuits, synaptic stiffness had a lognormal-like distribution, hinting a possible regulation of stiffness by processes involved in neural circuit function. In further support of this possibility, we observed that synaptic stiffness was correlated with spine size, a quantity known to correlate with synaptic strength. Using established stages of the long-term potentiation timeline and theoretical models of adhesion cluster dynamics, we developed a biophysical model of the synapse that not only explains extreme stiffness of synapses, their statistical distribution, and correlation with spine size, but also offers an explanation to how early biomolecular and structural changes during functional potentiation could lead to strengthening of synaptic adhesion. According to this model, synaptic stiffness serves as an indispensable physical messenger, feeding information back to synaptic adhesion molecules to facilitate maintenance of synaptic adhesion.

biophysics↗

bioRxiv2026

FoxP transcription factors are required for peripheral nervous system development

The FoxP family of transcription factors has been linked to neurodevelopmental disorders. FoxP1 and FoxP2 were identified as genes associated with autism spectrum disorders (ASD). FoxP1, FoxP2, and FoxP4 are expressed in many brain regions, including the cerebellum that has been of particular interest in the context of ASD. However, their role in the development of the peripheral nervous system (PNS) has been neglected. In view of the fact that a majority of ASD patients show some signs of sensory perception deficits that could go beyond the central nervous system, we focused on neural circuit formation in the PNS. Our in vivo and in vitro studies revealed a role of all three FoxP transcription factors in neural circuit formation in the hindlimb of the chicken embryo. Silencing of FoxP genes altered motor axon guidance and also impacted neural crest cell migration. This in turn resulted in aberrant formation of dorsal root ganglia and deficits in neural circuits in the PNS. Taken together, our results are in line with the hypothesis that some of the sensory perception deficits in ASD patients, either hyper- or hyposensitivity, are due to aberrant neural circuits in the PNS.

neuroscience↗

bioRxiv2026

A biologically-grounded cerebellar spiking network model with realistic synaptic transmission captures complex circuit dynamics.

Cerebellar neural circuit dynamics rely on a rich repertoire of synaptic and excitability mechanisms, which are thought to determine network computation in physiological and pathological conditions. In this work, we develop and validate a biologically-grounded spiking neural network of the cerebellar cortex, embedding key mechanisms of cellular excitability and synaptic transmission, and assess their impact on signal processing. Neuronal input-output functions, short-term synaptic plasticity, receptor-specific kinetics, and NMDA channel voltage-dependent gating were calibrated against detailed multicompartmental models through automatic tuning procedures. Incorporating these realistic biological properties allowed the network model to simulate key features observed in recordings from acute cerebellar slices. The neuronal discharge and local field potentials elicited by mossy fiber stimulation faithfully reproduced the natural patterns with millisecond precision. Then, selective receptor switch-off revealed the contribution of NMDA, GABA, and AMPA receptors to the frequency-dependent input-output function of the granular layer and Purkinje cells, linking previous empirical findings to specific synaptic mechanisms. This model combines high computational performance with biological realism and offers a computationally efficient framework to investigate neurophysiological phenomena and the neural correlates of behavior in large-scale long-lasting simulations, such as those needed to address the neural underpinnings of learning and of cerebellar pathologies.

neuroscience↗

bioRxiv2019

Generation of viral vectors specific to neuronal subtypes of targeted brain regions by Enhancer-Driven Gene Expression (EDGE)

Understanding brain function requires understanding neural circuits at the level of specificity at which they operate. While recent years have seen the development of a variety of remarkable molecular tools for the study of neural circuits, their utility is currently limited by the inability to deploy them in specific elements of native neural circuits, i.e. particular neuronal subtypes. One can obtain a degree of specificity with neuron-specific promoters, but native promoters are almost never sufficiently specific restricting this approach to transgenic animals. We recently showed that one can obtain transgenic mice with augmented anatomical specificity in targeted brain regions by identifying cis-regulatory elements (i.e. enhancers) uniquely active in those brain regions and combining them with a heterologous promoter, an approach we call EDGE (Enhancer-Driven Gene Expression). Here we extend this strategy to the generation of viral (rAAV) vectors, showing that when combined with the right minimal promoter they largely recapitulate the specificity seen in the corresponding transgenic lines in wildtype animals, even of another species. Because active enhancers can be identified in any tissue sample, this approach promises to enable the kind of circuit-specific manipulations in any species. This should not only greatly enhance our understanding of brain function, but may one day even provide novel therapeutic avenues to correct the imbalances in neural circuits underlying many disorders of the brain.

neuroscience↗

bioRxiv2020

Astrocytes close a critical period of motor circuit plasticity

Critical periods - brief intervals where neural circuits can be modified by sensory input - are necessary for proper neural circuit assembly. Extended critical periods are associated with neurodevelopmental disorders, including schizophrenia and autism; however, the mechanisms that ensure timely critical period closure remain unknown. Here, we define the extent of a critical period in the developing Drosophila motor circuit, and identify astrocytes as essential for proper critical period termination. During the critical period, decreased activity produces larger motor dendrites with fewer inhibitory inputs; conversely, increased motor neuron activity produces smaller motor dendrites with fewer excitatory inputs. Importantly, activity has little effect on dendrite morphology after critical period closure. Astrocytes invade the neuropil just prior to critical period closure, and astrocyte ablation prolongs the critical period. Finally, we use a genetic screen to identify astrocyte-motor neuron signaling pathways that close the critical period, including Neuroligin-Neurexin signaling. Reduced signaling destabilizes dendritic microtubules, increases dendrite dynamicity, and impairs locomotor behavior, underscoring the importance of critical period closure. Previous work defines astroglia as regulators of plasticity at individual synapses; here, we show that astrocytes also regulate large-scale structural plasticity to motor dendrite, and thus, circuit architecture to ensure proper locomotor behavior.

neuroscience↗

bioRxiv2024

Heterogeneous responses to embryonic critical period perturbations among different components of the Drosophila larval locomotor circuit

As developing neural circuits become functional, they undergo a phase of heightened plasticity that facilitates network tuning in response to intrinsic and/or extrinsic stimuli. These developmental windows are termed critical periods (CPs), because perturbations during, but not outside, the CP can lead to lasting changes, such as the formation of sub-optimal or unstable networks. How separate, but connected elements, within a network might respond differently to a CP perturbation is not well understood. To study this, we used the locomotor network of the Drosophila larva as a model and heat stress as a CP stimulus that has ecological relevance. When embryos experienced heat stress the subsequent development of their locomotor network is changed, creating larvae with reduced crawling speed and decreased network stability. Developing body wall muscles and central neurons are sensitive to heat stress perturbations during distinct, consecutive phases of embryogenesis. Within the CNS, transient embryonic CP perturbation leads to increased synaptic drive from premotor interneurons to motoneurons, which in turn adopt reduced excitability. In contrast, the peripheral neuromuscular junction maintains normal synaptic transmission, despite significant structural changes. Thus, connected elements respond differentially to a CP perturbation, suggesting a sequence, or hierarchy, of network adjustment during the CP.

neuroscience↗

bioRxiv2026

Competitive Olivocerebellar Input Selection Promotes Resilient Circuit Formation

Many neural circuits undergo competitive input selection, a process in which supernumerary connections compete for innervation territory on target cells. This process can create atypical circuits when functional inputs are favored over compromised ones. Yet, it is often unclear whether such atypical circuits are maladaptive or promote functional resilience. We investigated this using the olivocerebellar climbing fiber circuit, where multiple inputs compete to mono-innervate Purkinje cells. We found that eliminating neurotransmission from [~]50% of olivocerebellar neurons reduced climbing fibers competitiveness during input selection and decreased survival of parental inferior olive neurons. Conversely, functional climbing fibers expanded their innervation territory. Despite these atypical circuits, climbing-fiber-dependent motor control was only minimally affected and social behaviors were fully preserved. These results demonstrate that neurotransmission-dependent competition promotes resilient circuits formation, maintaining complex behaviors even when a large proportion of inputs to the cerebellum are developmentally compromised.

neuroscience↗

bioRxiv2019

Timing and Duration of Gbx2 Expression Delineates Thalamocortical and Dopaminergic Medial Forebrain Bundle Circuitry

Gene expression is a dynamic process, which is highly coordinated during development to ensure the proper allocation and identity of neuronal cell types within the brain. Equally important during neurodevelopment is how cohorts of neurons establish axonal projections that innervate terminal target sites. We sought to bridge the temporal dynamics of gene expression, within a specific genetic lineage, to the establishment of neuronal circuits derived from cohorts of the lineage-specific progenitors. A central goal was to be able to accomplish genetic inducible circuit mapping non-invasively and with commonly available CreER/loxP technology. Specifically, we genetically marked thalamic neuron progenitors that expressed the transcription factor Gbx2 at an early embryonic stage and tracked the formation of lineage-derived thalamocortical axons during embryogenesis. We then assessed the neural circuitry at an early postnatal stage. We show that the temporal specificity of lineage marking provides a high degree of clarity for following neural circuit development. We also determined that the onset and duration of gene expression can delineate subsets of neural circuits derived from a common lineage. For example, we uncovered a novel contribution of Gbx2-expressing progenitors to midbrain dopamine neurons and dopaminergic axons of the medial forebrain bundle. We anticipate that this system can be instructive in elucidating changes in neural circuit development in both normal development and in mutant mice in which neural circuit formation is altered.

neuroscience↗

bioRxiv2021

Corticostriatal suppression of appetitive Pavlovian conditioned responding

The capacity to suppress learned responses is essential for animals to adapt in dynamic environments. Extinction is a process by which animals learn to suppress conditioned responding when an expected outcome is omitted. The infralimbic cortex (IL) to nucleus accumbens shell (NAcS) neural circuit is implicated in suppressing conditioned responding after extinction, especially in the context of operant cocaine-seeking behaviour. However, the role of the IL-to-NAcS neural circuit in the extinction of responding to appetitive Pavlovian cues is unknown and the psychological mechanisms involved in response suppression following extinction are unclear. We trained rats to associate a 10 s auditory conditioned stimulus (CS; 14 trials per session) with a sucrose unconditioned stimulus (US; 0.2 mL per CS) in a specific context and then, following extinction in a different context, precipitated a renewal of CS responding by presenting the CS alone in the original Pavlovian conditioning context. Unilateral, optogenetic stimulation of the IL-to-NAcS circuit selectively during CS trials suppressed renewal. In a separate experiment, IL-to-NAcS stimulation suppressed CS responding regardless of prior extinction and impaired extinction retrieval. Finally, IL-to-NAcS stimulation during the CS did not suppress the acquisition of Pavlovian conditioning but was required for the subsequent expression of CS responding. These results are consistent with multiple studies showing that the IL-to-NAcS neural circuit is involved in the suppression of operant cocaine-seeking, extending these findings to appetitive Pavlovian cues. The suppression of appetitive Pavlovian responding following IL-to-NAcS circuit stimulation does not, however, appear to require an extinction-dependent process. SIGNIFICANCE STATEMENTExtinction is a form of inhibitory learning through which animals learn to suppress conditioned responding in the face of non-reinforcement. We investigated the role of infralimbic (IL) cortex inputs to the nucleus accumbens shell (NAcS) in the extinction of responding to appetitive Pavlovian cues and the psychological mechanisms involved in response suppression following extinction. Using in vivo optogenetics, we found that stimulating the IL-to-NAcS neural circuit suppressed context-induced renewal of conditioned responding after extinction. In a separate experiment, stimulating the IL-to-NAcS circuit suppressed conditioned responding in an extinction-independent manner. These findings can be leveraged by future research aimed at understanding how corticostriatal circuits contribute to behavioural flexibility and mental disorders that involve the suppression of learned behaviours.

neuroscience↗

bioRxiv2026

Wireless Magnetomechanical Stimulation of Targeted Vagal Gut-Brain Circuits

Causal manipulation of gut-brain neural circuits empowers studies of metabolism and interoception. However, the anatomy and cytoarchitecture of peripheral ganglia relaying gut-brain circuits pose challenges to deployment of optical or electrical stimulation probes. To enable implant-free, cell-type specific, and temporally precise control of defined gut-brain pathways, we develop a neuromodulation platform based on magnetic nanodiscs (MNDs) targeted to peripheral neurons via genetically delivered anchoring moieties. The anchored MNDs selectively transduce externally applied weak magnetic fields to mechanical torque, thereby activating endogenous mechanosensitive pathways in specified cell types with sub-second latency. When targeted to nodose ganglia neurons expressing oxytocin or glucagon-like peptide 1 receptors, MND-mediated stimulation enables robust and reversible activation of gut-brain signaling, which engages hindbrain satiety circuits and regulates feeding behavior. These findings establish MND-mediated stimulation as a genetically targetable, implant-free strategy for modulating gut-brain neural circuits and highlight its potential in studies of brain-body physiology and bioelectronic medicines.

bioengineering↗

bioRxiv2022

AAV11 permits efficient retrograde targeting of projection neurons

Viral tracers that permit efficient retrograde targeting of projection neurons are powerful vehicles for structural and functional dissections of the neural circuit and for the treatment of brain diseases. Recombinant adeno-associated viruses (rAAVs) are the most potential candidates because they are low-toxic with high-level transgene expression and minimal host immune responses. Currently, some rAAVs based on capsid engineering for retrograde tracing have been widely used in the analysis and manipulation of neural circuits, but suffer from brain area selectivity and inefficient retrograde transduction in certain neural connections. Here, we discovered that the recombinant adeno-associated virus 11 (rAAV11) exhibits potent retrograde labeling of projection neurons with enhanced efficiency to rAAV2-retro in some neural connections. Combined with calcium recording technology, rAAV11 can be used to monitor neuronal activities by expressing Cre recombinase or calcium-sensitive functional probe. In addition, we further showed the suitability of rAAV11 for astrocyte targeting. These properties make rAAV11 a promising tool for the mapping and manipulation of neural circuits and gene therapy of some neurological and neurodegenerative disorders. HighlightsO_LINaturally occurring AAV serotype capsid exhibits robust retrograde functionality C_LIO_LIImproved distribution properties and retrograde transport efficiency C_LIO_LICan express Cre recombinase or calcium-sensitive functional probe for neural circuits monitoring C_LIO_LICan specifically target astrocytes C_LI

neuroscience↗