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bioRxiv2016

Contributions of hippocampus and striatum to memory-guided behavior depend on past experience

The hippocampal and striatal memory systems operate independently and in parallel in supporting spatial and response learning, respectively, when animals are explicitly trained in one task. Here, we investigated whether this principle continues to hold when animals are concurrently trained in two types of tasks. Rats were trained on a plus maze in either a spatial navigation or a cue response task (individual training), while a third set of rats acquired both (concurrent training). Subsequently, the rats underwent either sham surgery or neurotoxic lesions of the hippocampus (HPC), medial dorsal striatum (DSM) or lateral dorsal striatum (DSL), followed by retention testing. Finally, rats in the individual training condition also acquired the novel other task. When rats learned one task, HPC and DSL selectively supported spatial navigation cue response, respectively. However, when rats learned both tasks, HPC and DSL additionally supported the behavior incongruent with the processing style of the corresponding memory system. DSM significantly contributed to performance regardless of task or training procedure. Experience with the cue response task facilitated subsequent spatial learning, while experience with spatial navigation delayed both simultaneous and subsequent response learning. These findings suggest that multiple principles govern the interactions among memory systems.\n\nSignificance StatementCurrently, we distinguish among several types of memories, each supported by a distinct neural circuit. The memory systems are thought to operate independently and in parallel. Here, we demonstrate that the hippocampus and the dorsal striatum memory systems indeed operate independently and in parallel when rats learn one type of task at a time, but interact co-operatively and in synergism when rats concurrently learn two types of tasks. Furthermore, new learning is modulated by past experiences. These results can be explained by a model in which independent and parallel information processing that occurs in the separate memory-related neural circuits is supplemented by information transfer between the memory systems at the level of the cortex.

Animal Behavior and Cognition↗

bioRxiv2023

Developmental remodeling repurposes larval neurons for sexual behaviors in adult Drosophila

Most larval neurons in Drosophila are repurposed during metamorphosis for functions in adult life, but their contribution to the neural circuits for sexually dimorphic behaviors is unknown. Here, we identify two interneurons in the nerve cord of adult Drosophila females that control ovipositor extrusion, a courtship rejection behavior performed by mated females. We show that these two neurons are present in the nerve cord of larvae as mature, sexually monomorphic interneurons. During pupal development, they acquire the expression of the sexual differentiation gene, doublesex, undergo doublesex-dependent programmed cell death in males, and are remodeled in females for functions in female mating behavior. Our results demonstrate that the neural circuits for courtship in Drosophila are built in part using neurons that are sexually reprogrammed from former sex-shared activities in larval life.

neuroscience↗

bioRxiv2025

A Developmental Atlas of the Drosophila Nerve Cord Uncovers a Global Temporal Code for Neuronal Identity

The assembly of functional neural circuits relies on the generation of diverse neural types with precise molecular identity and connectivity. Unlocking general principles of neuronal specification and wiring across the nervous system requires a systematic and high-resolution characterisation of its diversity, recently enabled by advances in single-cell transcriptomics and connectomics. However, linking the molecular identity of neurons to circuit architecture remains a key challenge. Here, we present a high-resolution developmental transcriptional atlas for the Drosophila melanogaster nerve cord, the central hub for sensory-motor circuits. With an unprecedented 38x aggregate coverage relative to its reference connectome1,2, our atlas captures extensive molecular diversity and enables robust alignment to the adult connectome. We identified three developmental principles underlying neuronal diversity in the nerve cord. First, timing of neurogenesis shapes diversification of molecular identity: embryonic-born neurons diverge faster than larval-born neurons, as also observed in the adult connectome. Second, 17 transcription factors common to neurons from all lineages provide a global molecular identity code for birth order. Lastly, by mapping sex-specific transcriptional profiles to the connectome, we uncovered female-specific apoptosis and transcriptional divergence as key global drivers of sex-specification. By revealing key organisational axes of molecular identity, this atlas opens new avenues to dissect the molecular mechanisms underpinning the development and evolution of neural circuits.

neuroscience↗

bioRxiv2025

Mapping the projectional architecture of the mouse midbrain dopaminergic system using cell type-specific barcoding

Brain-wide neural circuits are formed by the diverse axonal branching patterns of neurons of different cell types. Here we introduce POINTseq (projections of interest by sequencing), a cell type-specific barcoded connectomics method that uses selective barcoding and sequencing to rapidly map single-cell projections of a cell type of interest for thousands of neurons per animal. POINTseq leverages pseudotyping of Sindbis virus and a specific alphavirus-cellular receptor pair to make Sindbis infections cell type specific. It thus integrates MAPseq-style high-throughput barcoded projection mapping with the established viral-genetic neural circuit analysis toolbox. We validated POINTseq by mapping genetically and projection-defined cell populations in the mouse motor cortex. We then applied POINTseq to midbrain dopaminergic neurons and reconstructed the brain-wide single-cell projections of 5,902 dopaminergic neurons in ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). These neurons cluster into over 25 connectomic cell types, vastly exceeding the known diversity of dopaminergic cells, and form stereotyped projection motifs that may mediate parallel dopamine signaling. This data constitutes the anatomical substrate on which the diverse functions of dopamine in the brain are built. HIGHLIGHTSO_LIWe develop POINTseq, which uses pseudotyped Sindbis virus and cell type-specific expression of a viral receptor for cell type-specific barcoding. C_LIO_LIPOINTseq enables massively multiplexed single-cell projection mapping of cell types of interest. C_LIO_LIWe map the brain-wide projections of 5,902 individual VTA and SNc dopaminergic neurons. C_LIO_LIVTA and SNc dopaminergic neurons form over 25 connectomic cell types. C_LIO_LIProjections are organized into stereotyped motifs that may mediate the distinct functions of dopamine. C_LI

neuroscience↗

bioRxiv2023

Two conserved vocal central pattern generators broadly tuned for fast and slow rates generate species-specific vocalizations in Xenopus clawed frogs

Across phyla, species-specific vocalizations are used by males to attract females. Functional analyses of the neural circuitry underlying behavior have been difficult, particularly in vertebrates. However, using an ex vivo brain preparation that produces fictive vocalizations, we previously identified anatomically distinct fast and slow central pattern generators (CPGs) that drive the fast and slow clicks of male courtship calls in male African clawed frogs, Xenopus laevis. To gain insight into the evolution of neural circuits underlying courtship calls, we extended this approach to four additional species. Here, we show that although the exact rate and duration of the clicks are unique to each species, fast and slow CPGs identified in male X. laevis are conserved across species. Further, we show that the development of fast CPGs depends on testosterone in a species-specific manner: testosterone facilitates the development of fast CPGs in a species with a courtship call containing fast clicks, but not in a species with a courtship call made entirely of slow clicks. Finally, we showed that, unlike other vestigial neural circuits that remain latent, the fast CPGs are not inherited by all species; rather, they are possessed only by the species that produce fast clicks. The results suggest that species-specific calls of the genus Xenopus have evolved by utilizing conserved fast or slow CPGs that are broadly tuned to generate fast or slow trains of clicks, the development of which appear to be regulated by a strategic expression of testosterone receptors in the brain of each species.

neuroscience↗

bioRxiv2019

Canonical brain computations account for perceived sound source location

Sound localization in reverberant environments is a difficult task that human listeners perform effortlessly. Many neural mechanisms have been proposed to account for this behavior. Generally they rely on emphasizing localization information at the onset of the incoming sound while discarding localization cues that arrive later. We modelled several of these mechanisms using neural circuits commonly found in the brain and tested their performance in the context of experiments showing that, in the dominant frequency region for sound localisation, we have a preference for auditory cues arriving during the rising slope of the sound energy (Dietz et al., 2013). We found that both single cell mechanisms (onset and adaptation) and population mechanisms (lateral inhibition) were easily able to reproduce the results across a very wide range of parameter settings. This suggests that sound localization in reverberant environments may not require specialised mechanisms specific to perform that task, but could instead rely on common neural circuits in the brain. This would allow for the possibility of individual differences in learnt strategies or neuronal parameters. This research is fully reproducible, and we made our code available to edit and run online via interactive live notebooks.

neuroscience↗

bioRxiv2025

Personalized mapping of inhibitory spinal circuits via neural decoding of high-density electromyography and in silico modelling

Studying human motoneuron activity through electromyography (EMG) can yield insights into the operation of fundamental spinal cord microcircuits. Traditional surface and needle electromyography (EMG) methodologies have limited capacity to shed light on the diversity of motor unit (MU) control strategies that may be unique to each individual. Here, we employed high-density surface EMG (HDsEMG) to sample multiple MUs per subject to investigate the dynamics of inhibitory spinal microcircuits in both upper and lower limb control. We characterised the net inhibition as a function of individual MU firing rates, revealing subject-specific relationships. In silico modelling replicated these experimental characteristics and suggested that properties of the inhibitory currents rather than motoneuron size are responsible for net functional inhibition. Our results show that HDsEMG can highlight distinct control strategies across circuits and motor pools, revealing subject-specific properties of inhibitory spinal microcircuits. TEASERHigh-density surface EMG electrodes can reveal the functional properties of inhibitory spinal circuits

neuroscience↗

bioRxiv2018

Verifying, Challenging, and Discovering New Synapses among Fully EM-Reconstructed Neurons in the Leech Ganglion

Neural circuits underpin the production of animal behavior, largely based upon the precise pattern of synaptic connectivity among the neurons involved. For large numbers of neurons, determining such \"connectomes\" by direct physiological means is difficult, as physiological accessibility is ultimately required to verify and characterize the function of synapses. We collected a volume of images spanning an entire ganglion of the juvenile leech nervous system via serial blockface electron microscopy (SBEM). We validated this approach by reconstructing a well-characterized circuit of motor neurons involved in the swimming behavior of the leech by locating the synapses among them. We confirm that there are multiple synaptic contacts between connected pairs of neurons in the leech, and that these synapses are widely distributed across the region of neuropil in which the neurons arbors overlap. We verified the anatomical existence of connections that had been described physiologically among longitudinal muscle motor neurons. We also found that some physiological connections were not present anatomically. We then drew upon the SBEM dataset to design additional physiological experiments. We reconstructed an uncharacterized neuron and one of its presynaptic partners identified from the SBEM dataset. We subsequently interrogated this cell pair via intracellular electrophysiology in an adult ganglion and found that the anatomically-discovered synapse was also functional physiologically. Our findings demonstrate the value of combining a connectomics approach with electrophysiology in the leech nervous system.\n\nSignificance StatementThe function of any nervous system depends on the arrangement of its component neurons into circuits. Determining this precise pattern requires an account of which neurons are linked by synapses, and where. Here we use serial electron microscopy to confirm, challenge, and discover synapses in the neuropil of one ganglion from a juvenile leech. Relying on the homology of the ganglion from animal to animal, we demonstrate that we can identify synapses we knew existed from previous physiological work, and that we can confirm a new anatomically-discovered synapse by subsequently recording from the same neurons in a different animal. Here we show how analyses of anatomical detail and physiologically determined interactions complementarily yield insight into how neural circuits produce behavior.

neuroscience↗

bioRxiv2021

Elimination of glutamatergic transmission from Hb9 interneurons does not impact treadmill locomotion

The spinal cord contains neural circuits that can produce the rhythm and pattern of locomotor activity. It has previously been postulated that a rhythmogenic population of glutamatergic neurons, termed Hb9 interneurons, contributes to this rhythmogenesis. The homeobox gene, Hb9, is expressed in these interneurons as well as motor neurons. We developed a mouse line in which cre recombinase activity is inducible in neurons expressing Hb9. We then used this line to eliminate vesicular glutamate transporter 2 from Hb9 interneurons, and found that there were no deficits in treadmill locomotion. We conclude that glutamatergic neurotransmission by Hb9 interneurons is not required for locomotor rhythmogenesis. The role of these neurons in neural circuits remains elusive.

neuroscience↗

bioRxiv2024

2P-NucTag: on-demand phototagging for molecular analysis of functionally identified cortical neurons

Neural circuits are characterized by genetically and functionally diverse cell types. A mechanistic understanding of circuit function is predicated on linking the genetic and physiological properties of individual neurons. However, it remains highly challenging to map the molecular properties onto functionally heterogeneous neuronal subtypes in mammalian cortical circuits in vivo. Here, we introduce a high-throughput two-photon nuclear phototagging (2P-NucTag) approach for on-demand and indelible labeling of single neurons via a photoactivatable red fluorescent protein following in vivo functional characterization in behaving mice. Using this novel function-forward pipeline to selectively label and transcriptionally profile previously inaccessible place and silent cells in the hippocampus of behaving mice, we identify unexpected differences in gene expression between these hippocampal pyramidal neurons with distinct spatial coding properties. Thus, 2P-NucTag opens a new way to uncover the molecular principles that govern the functional organization of neural circuits. One-Sentence Summary2P-NucTag - A novel high-throughput on-demand phototagging approach to identify selective gene expression of functionally distinct neurons in vivo in behaving animals.

neuroscience↗

bioRxiv2018

PRL-1 is required for neuroprotection against olfactory CO2 stimulation in Drosophila

The Mammalian phosphatase of regenerating liver (PRL) family is primarily recognized for its oncogenic properties. Here we found that in Drosophila, loss of prl-1 resulted in CO2-induced brain disorder presented as irreversible wing hold up with enhancement of Ca2+ responses at the neuron synaptic terminals. Overexpression of Prl-1 in the nervous system could rescue the mutant phenotype. We show that Prl-1 is particularly expressed in CO2-responsive neural circuit and the higher brain centers. Ablation of the CO2 olfactory receptor, Gr21a, suppressed the mutant phenotype, suggesting that CO2 acts as a neuropathological substrate in absence of Prl-1. Further studies found that the wing hold up is an obvious consequence upon knockdown of Uex, a magnesium transporter, which directly interacts with Prl-1. Conditional expression of Uex in the nervous system could rescue the phenotype of prl-1 mutants. We demonstrate that Uex acts genetically downstream of Prl-1. Our findings provide important insights into mechanisms of Prl-1 protection against olfactory CO2 stimulation induced brain disorder at the level of detailed neural circuits and functional molecular connections.

neuroscience↗

bioRxiv2019

Defined cell types in superior colliculus make distinct contributions to prey capture behavior in the mouse

The superior colliculus (SC) mediates rapid orienting to visual stimuli across species. To determine the specific circuits within the SC that drive orienting and approach behavior toward appetitive stimuli, we explored the role of three genetically defined cell types in mediating prey capture in mice. Chemogenetic inactivation of two classically defined cell types, the wide-field (WF) and narrow-field (NF) vertical neurons, revealed that they are involved in distinct aspects of prey capture. WF neurons were required for rapid prey detection and distant approach initiation, whereas NF neurons were required for continuous and accurate orienting during pursuit. In contrast, prey capture did not require parvalbumin-expressing (PV) neurons that have previously been implicated in fear responses. The visual coding of WF and NF cells in the awake mouse and their projection targets were consistent with their roles in prey detection versus pursuit. Thus, our studies link specific neural circuit connectivity and function with stimulus detection and orienting behavior, providing insight into visuomotor and attentional mechanisms mediated by superior colliculus.\n\nHighlightsO_LIThis study provides the first demonstration of the role of specific cell populations in the superior colliculus in orienting and approach behavior.\nC_LIO_LIA genetically targeted population of wide-field vertical neurons in the superior colliculus is required for rapid prey detection and initiation of long-distance approaches.\nC_LIO_LIA genetically targeted population of narrow-field vertical neurons is required for approach initiation, accurate targeting, and approach continuity.\nC_LIO_LIVisual response properties and projection targets of these cells are consistent with their role in prey capture, linking neural circuit connectivity and function with behavior.\nC_LI

neuroscience↗

bioRxiv2021

Compensatory variability in network parameters enhances memory performance in the Drosophila mushroom body

Neural circuits use homeostatic compensation to achieve consistent behaviour despite variability in underlying intrinsic and network parameters. However, it remains unclear how compensation regulates variability across a population of the same type of neurons within an individual, and what computational benefits might result from such compensation. We address these questions in the Drosophila mushroom body, the flys olfactory memory center. In a computational model, we show that memory performance is degraded when the mushroom bodys principal neurons, Kenyon cells (KCs), vary realistically in key parameters governing their excitability, because the resulting inter-KC variability in average activity levels makes odor representations less separable. However, memory performance is rescued while maintaining realistic variability if parameters compensate for each other to equalize KC average activity. Such compensation can be achieved through both activity-dependent and activity-independent mechanisms. Finally, we show that correlations predicted by our models compensatory mechanisms appear in the Drosophila hemibrain connectome. These findings reveal compensatory variability in the mushroom body and describe its computational benefits for associative memory. Significance statementHow does variability between neurons affect neural circuit function? How might neurons behave similarly despite having different underlying features? We addressed these questions in neurons called Kenyon cells, which store olfactory memories in flies. Kenyon cells differ among themselves in key features that affect how active they are, and in a model of the flys memory circuit, adding this inter-neuronal variability made the model fly worse at learning the values of multiple odors. However, memory performance was rescued if compensation between the variable underlying features allowed Kenyon cells to be equally active on average, and we found the hypothesized compensatory variability in real Kenyon cells anatomy. This work reveals the existence and computational benefits of compensatory variability in neural networks.

neuroscience↗

bioRxiv2023

Investigating social communication in mice: a Two-intruders test approach

Understanding the complex dynamics of social communication behaviors, such as exploration, communication, courtship, mating, and aggression in animal models is crucial to reveal key neural and hormonal mechanisms underlying these behaviors. The Two-intruders test is designed to investigate residents behavior toward a male and female intruders. During this test imitating natural conditions, several aspects of social interaction were investigated: exploration, courtship, mating, and aggressive behavior. As mating and aggression involve overlapping neural circuits, the behavioral setup testing both behaviors is best at reflecting their competitive nature. Our findings demonstrate that male mice exhibit strong preference to communicate with a female intruder, which correlates with baseline testosterone levels of test males. Relevant female preference in the Two-intruder test was also found in BALB/c males. Behavioral breakdown revealed the anogenital sniffing as a key behavioral feature that discriminates test male behavior toward intruders of different genders. At the same time, female preference was accompanied by neuronal activation in the ventromedial hypothalamus. We demonstrate that odor recognition underlies preference toward females in male residents, as experimental anosmia reduced communication with a female intruder. However, there was no correlation between female animal preference in the contact Two-intruder test and smell preference in the social odor preference test. We assume the Two-intruders test setup to be a useful tool to study the neurological basis of social communication in animal models. Combined with odor preference tests, this experimental paradigm can help to decipher neural circuits involved in social deficiency phenotypes in animal models of human diseases. Significance StatementThe Two-intruders test proves to be a highly reproducible and robust approach to assess social communication in mice. We demonstrate that the results obtained in this experimental setting replicate in different mouse groups and strains. This test is indispensable in studies assessing the competitive nature of male- and female-driven behaviors and the underlying neural mechanisms. Residents social interactions in the described here set up reflects odor processing and circulating testosterone - the key physiological drivers of animal communication with conspecifics. While easy to perform, this test provides a broad spectrum of behavioral patterns to study in the models of complex neurological diseases. Largely overseen in the literature as compared to the resident-intruder setup, the Two-intruders test can provide superior performance when used to understand the neural mechanisms of mating, aggression and social communication.

neuroscience↗

bioRxiv2021

Carbon Fiber Electrodes for Intracellular Recording and Stimulation

To understand neural circuit dynamics, it is critical to manipulate and record from many neurons, ideally at the single neuron level. Traditional recording methods, such as glass microelectrodes, can only control a small number of neurons. More recently, devices with high electrode density have been developed, but few of them can be used for intracellular recording or stimulation in intact nervous systems, rather than on neuronal cultures. Carbon fiber electrodes (CFEs) are 8 micron-diameter electrodes that can be organized into arrays with pitches as low as 80 {micro}m. They have been shown to have good signal-to-noise ratios (SNRs) and are capable of stable extracellular recording during both acute and chronic implantation in vivo in neural tissue such as rat motor cortex. Given the small fiber size, it is possible that they could be used in arrays for intracellular stimulation. We tested this using the large identified and electrically compact neurons of the marine mollusk Aplysia californica. The cell bodies of neurons in Aplysia range in size from 30 to over 250 {micro}m. We compared the efficacy of CFEs to glass microelectrodes by impaling the same neurons cell body with both electrodes and connecting them to a DC coupled amplifier. We observed that intracellular waveforms were essentially identical, but the amplitude and SNR in the CFE were lower than in the glass microelectrode. CFE arrays could record from 3 to 8 neurons simultaneously for many hours, and many of these recordings were intracellular as shown by recording from the same neuron using a glass microelectrode. Stimulating through CFEs coated with platinum-iridium had stable impedances over many hours. CFEs not within neurons could record local extracellular activity. Despite the lower SNR, the CFEs could record synaptic potentials. Thus, the stability for multi-channel recording and the ability to stimulate and record intracellularly make CFEs a powerful new technology for studying neural circuit dynamics.

neuroscience↗

bioRxiv2021

Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making

The primate prefrontal cortex (PFC) is situated at the core of higher brain functions by linking and cooperating with the caudate nucleus (CD) and mediodorsal thalamus (MD) via neural circuits. However, the distinctive roles of these prefronto-subcortical pathways remain elusive. Combining in vivo neuronal projection mapping with chemogenetic synaptic silencing, we reversibly dissected key pathways from PFC to the CD and MD individually in single monkeys. We found that silencing the bilateral PFC-MD projections, but not the PFC-CD projections, impaired performance in a spatial working memory task. Conversely, silencing the unilateral PFC-CD projection, but not the PFC-MD projection, altered preference in a free-choice task. These results revealed dissociable roles of the prefronto-subcortical pathways in working memory and decision-making, representing the technical advantage of imaging-guided pathway-selective chemogenetic manipulation for dissecting neural circuits underlying cognitive functions in primates.

neuroscience↗

bioRxiv2026

Acceleration and Velocity Dissociate Temporal Phases of Postural Control in Rhesus Macaques

Maintaining balance requires the nervous system to transform sensory signals about unexpected postural perturbations into precisely timed motor commands. Although human studies have established that postural responses unfold in distinct temporal phases, how specific kinematic variables structure these phases during rotational perturbations remains unresolved, because angular acceleration and velocity are typically confounded. Here, we developed a rhesus macaque model of postural control that independently manipulates angular acceleration and peak velocity during transient pitch and roll tilts in monkeys of either sex. By simultaneously measuring head kinematics--directly relevant to vestibular signaling--and center-of-pressure dynamics, we quantified how sensory inputs and motor outputs evolve across successive phases of the postural response. We show that short-latency postural responses (<100 ms) are primarily governed by angular acceleration, whereas medium-latency responses (100-200 ms) scale with angular velocity. This dissociation was robust across perturbation axes and accompanied by axis-dependent control strategies: roll tilts elicited constrained head motion consistent with active stabilization in space, whereas pitch tilts produced more compliant, platform-following behavior. Together, these findings identify distinct kinematic variables governing successive phases of balance control and establish a primate framework for linking neural circuit activity to the temporal organization of postural responses. Significance StatementMaintaining balance requires transforming sensory signals about unexpected body motion into precisely timed motor commands. Progress in understanding this process has been limited because angular acceleration and velocity are inherently coupled during rotational perturbations. Here, using a rhesus macaque model, we dissociate these kinematic variables and show that they govern distinct temporal phases of postural control: angular acceleration determines short-latency (<100 ms) responses, whereas angular velocity shapes medium-latency (100-200 ms) adjustments. We further demonstrate axis-dependent postural strategies that parallel those observed in humans. Together, these findings resolve a longstanding confound in balance research and establish a primate framework that will enable future studies to link neural circuit activity to the biomechanics of postural control.

neuroscience↗

bioRxiv2026

Native receptor-targeted chemogenetics enables cell-type-specific inhibition of endogenous receptors in freely moving mice

Understanding brain function requires tools that allow precise manipulation of receptor signaling in defined cell types within intact neural circuits. Optogenetics and conventional chemogenetic approaches primarily enable cell-type-specific control of neuronal excitability using engineered receptors or ion channels. However, direct and reversible inhibition of endogenous neurotransmitter receptors in defined cell types has remained technically inaccessible. Here, we introduce native receptor-targeted chemogenetics (NARCH), a chemogenetic strategy that integrates structure-guided receptor engineering with allosteric ligand design to achieve reversible and temporally precise inhibition of endogenous receptor signaling with cell-type specificity in vivo. By applying NARCH to metabotropic glutamate receptor 1 (mGlu1), we demonstrate that mGlu1 signaling in cerebellar Purkinje cells is required for stabilization of motor learning across training sessions in freely moving mice. NARCH thus establishes a receptor-level chemogenetic framework for causal analysis of neural circuits and behavior.

neuroscience↗