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bioRxiv2016

Oscillatory integration windows in neurons

Oscillatory synchrony among neurons occurs in many species and brain areas, and has been proposed to help neural circuits process information. One hypothesis states that oscillatory input creates cyclic integration windows: specific times in each oscillatory cycle when postsynaptic neurons become especially responsive to inputs. With paired local field potential (LFP) and intracellular recordings and controlled stimulus manipulations we directly tested this idea in the locust olfactory system. We found that inputs arriving in Kenyon cells (KCs) sum most effectively in a preferred window of the oscillation cycle. With a computational model, we found that the non-uniform structure of noise in the membrane potential helps mediate this process. Further experiments performed in vivo demonstrated that integration windows can form in the absence of inhibition and at a broad range of oscillation frequencies. Our results reveal how a fundamental coincidence-detection mechanism in a neural circuit functions to decode temporally organized spiking.

neuroscience↗

bioRxiv2022

Characterizing ketamine-induced dissociation using human intracranial neurophysiology: brain dynamics, network activity, and interactions with propofol

Subanesthetic doses of ketamine produce rapid and sustained anti-depressant effects in patients with treatment-resistant depression. Unfortunately, the usefulness of ketamine as a treatment is limited by its potential for abuse because of psychotropic side effects such as dissociation. Understanding the brain dynamics and the neural circuits involved in ketamines effects could lend insight into improved therapies for depression with fewer adverse effects. It is believed that ketamine acts via NMDA receptor and hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels to produce changes in oscillatory brain dynamics. Here we show, in humans, a detailed description of the principal oscillatory changes in cortical and subcortical structures by administration of a subanesthetic dose of ketamine. Using recordings from intracranial electrodes, we found that ketamine increased gamma oscillations within prefrontal cortical areas and the hippocampus--structures previously implicated in ketamines antidepressant effects. Furthermore, our studies provide direct evidence of a ketamine-induced 3 Hz oscillation in posteromedial cortex that has been proposed as a mechanism for its dissociative effects. By analyzing changes in neural oscillations after the addition of propofol, whose GABAergic activity antagonizes ketamines NMDA-mediated disinhibition alongside a shared HCN1 inhibitory effect, we identified brain dynamics that could be attributed to NMDA-mediated disinhibition versus HCN1 inhibition. Overall, our results imply that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of novel brain dynamic biomarkers and therapeutics for depression.

neuroscience↗

bioRxiv2019

Multiplexed temporally focused light shaping through a GRIN lens for precise in-depth optogenetic photostimulation

In the past 10 years, the use of light has become irreplaceable for the optogenetic study and control of neurons and neural circuits. Optical techniques are however limited by scattering and can only see through a depth of few hundreds {micro}m in living tissues. GRIN lens based micro-endoscopes represent a powerful solution to reach deeper regions. In this work we demonstrate that cutting edge optical methods for the precise photostimulation of multiple neurons in three dimensions can be performed through a GRIN lens. By spatio-temporally shaping a laser beam in the two-photon regime we project several tens of targets, spatially confined to the size of a single cell, in a volume of 150x150x400 m3. We then apply such concept to the optogenetic stimulation of multiple neurons simultaneously in vivo in mice. Our work paves the way for an all-optical investigation of neural circuits at previously unattainable depths.

neuroscience↗

bioRxiv2024

Combinatorial expression of neurexin genes regulates glomerular targeting by olfactory sensory neurons

Precise connectivity between specific neurons is essential for the formation of the complex neural circuitry necessary for executing intricate motor behaviors and higher cognitive functions. While trans-interactions between synaptic membrane proteins have emerged as crucial elements in orchestrating the assembly of these neural circuits, the synaptic surface proteins involved in neuronal wiring remain largely unknown. Here, using unbiased single-cell transcriptomic and mouse genetic approaches, we uncover that the neurexin family of genes enables olfactory sensory neuron (OSNs) axons to form appropriate synaptic connections with their mitral and tufted (M/T) cell synaptic partners, within the mammalian olfactory system. Neurexin isoforms are differentially expressed within distinct populations of OSNs, resulting in unique pattern of neurexin expression that is specific to each OSN type, and synergistically cooperate to regulate axonal innervation, guiding OSN axons to their designated glomeruli. This process is facilitated through the interactions of neurexins with their postsynaptic partners, including neuroligins, which have distinct expression patterns in M/T cells. Our findings suggest a novel mechanism underpinning the precise assembly of olfactory neural circuits, driven by the trans-interaction between neurexins and their ligands.

developmental biology↗

bioRxiv2021

Central nervous system hypomyelination disrupts axonal conduction and behaviour in larval zebrafish

Myelination is essential for central nervous system (CNS) formation, health and function. As a model organism, larval zebrafish have been extensively employed to investigate the molecular and cellular basis of CNS myelination, due to their genetic tractability and suitability for non-invasive live cell imaging. However, it has not been assessed to what extent CNS myelination affects neural circuit function in zebrafish larvae, prohibiting the integration of molecular and cellular analyses of myelination with concomitant network maturation. To test whether larval zebrafish might serve as a suitable platform with which to study the effects of CNS myelination and its dysregulation on circuit function, we generated zebrafish myelin regulatory factor (myrf) mutants with CNS-specific hypomyelination and investigated how this affected their axonal conduction properties and behaviour. We found that myrf mutant larvae exhibited increased latency to perform startle responses following defined acoustic stimuli. Furthermore, we found that hypomyelinated animals often selected an impaired response to acoustic stimuli, exhibiting a bias towards reorientation behaviour instead of the stimulus-appropriate startle response. To begin to study how myelination affected the underlying circuitry, we established electrophysiological protocols to assess various conduction properties along single axons. We found that the hypomyelinated myrf mutants exhibited reduced action potential conduction velocity and an impaired ability to sustain high frequency action potential firing. This study indicates that larval zebrafish can be used to bridge molecular and cellular investigation of CNS myelination with multiscale assessment of neural circuit function.

neuroscience↗

bioRxiv2018

The CRUNCH model does not account for load-dependent changes in visuospatial working memory in older adults: Evidence for the file-drawer problem in neuroimaging

Numerous neuroimaging studies have shown that older adults tend to activate the brain to a greater extent than younger adults during the performance of a task. This is typically interpreted as evidence for cognitive compensation. The Compensation-Related Utilisation of Neural Circuits Hypothesis (CRUNCH) model is a highly influential model of compensation, and states that increased functional magnetic resonance imaging (fMRI) activity in older adults compared to younger adults should reverse at higher levels of task difficulty. We tested the CRUNCH model using a visuospatial working memory paradigm, and found that fMRI activity in older vs. younger adults was in the opposite direction to that predicted by the model. Given that the CRUNCH model is the predominant model of compensation, this result was surprising. We followed up our results with a systematic review of the CRUNCH in healthy ageing literature using p-curve analysis. We find evidence for selective reporting, or the file-drawer problem, in the cognitive compensation literature. Further experimental work is required to validate the CRUNCH model in cognitive ageing.\n\nAbbreviationsCRUNCH: compensation-related utilisation of neural circuits hypothesis; fMRI: functional magnetic resonance imaging\n\nHighlights- CRUNCH is the leading model of cognitive compensation in ageing\n- We find fMRI activity in old vs. young adults in opposite direction predicted by CRUNCH\n- We report quantitative evidence of selective reporting in CRUNCH literature

neuroscience↗

bioRxiv2025

Strategies to decipher neuron identity from extracellular recordings in the cerebellum of behaving non-human primates

Identification of neuron type is critical to understand computation in neural circuits through extracellular recordings in awake, behaving animal subjects. Yet, modern recording probes have limited power to resolve neuron type. Here, we leverage the well-characterized architecture of the cerebellar circuit to perform expert identification of neuron type from extracellular recordings in behaving non-human primates. Using deep-learning classifiers we evaluate the information contained in readily accessible extracellular features for neuron identification. Waveform, discharge statistics, anatomical layer, and functional interactions each can inform neuron labels for a sizable fraction of cerebellar units. Together, as inputs to a deep-learning classifier, the features perform even better. Our tools and methodologies, validated during smooth pursuit eye movements in the cerebellar floccular complex of awake behaving monkeys, can guide expert identification of neuron type during cerebellar-dependent tasks in behaving animals across species. They lay the groundwork for characterization of information processing in the cerebellar cortex. Impact statementTo understand how the brain performs computations in the service of behavior, we develop methods to link neuron type to functional activity within well-characterized neural circuits. Here, we show how features derived from extracellular recordings provide complementary information to disambiguate neuron identity in the cerebellar cortex.

neuroscience↗

bioRxiv2025

The human claustrum initiates networks for externally and internally driven task demands.

Cognitive control is believed to arise from interactions among multiple brain networks depending on task demands. Although several debilitating neuropsychiatric disorders are characterized by cognitive network dysfunction, the neural circuit mechanisms supporting task-dependent network activation are largely unknown. Because the claustrum possesses widespread connections with cortex and can synchronize distant cortical regions, we tested whether the claustrum activates task-dependent network states using fMRI during working memory (n = 420) and autobiographical memory (n = 35), tasks which elicit opposing responses from key cognitive control networks. In both tasks, the claustrum exhibited increased activity and excitatory influence on task-associated cognitive control network nodes, with corroborating underlying structural connectivity. The claustrum also displayed stronger excitatory effective connectivity during task performance and greater structural connectivity with task-related network nodes than regions prominently implicated in directing network states--the anterior insula and pulvinar. These findings establish a role for the claustrum in initiating network states for cognitive control. SignificanceCognitive functioning is supported by large-scale networks across the brain. Yet, the neural circuit mechanisms supporting task-dependent network activation are largely unknown. Circuit analyses using human functional and structural neuroimaging in this study found that the claustrum, a subcortical nucleus, activates during multiple cognitive tasks eliciting a wide range of network states, possesses strong anatomical connections with cognitive control network nodes, and exerts excitatory influence on task-associated network regions. These results establish the claustrum as a network activator subserving cognitive control.

neuroscience↗

bioRxiv2024

A single-cell transcriptomic atlas of sensory-dependent gene expression in developing mouse visual cortex

Sensory experience drives the refinement and maturation of neural circuits during postnatal brain development through molecular mechanisms that remain to be fully elucidated. One likely mechanism involves the sensory-dependent expression of genes that encode direct mediators of circuit remodeling within developing cells. However, while studies in adult systems have begun to uncover crucial roles for sensory-induced genes in modifying circuit connectivity, the gene programs induced by brain cells in response to sensory experience during development remain to be fully characterized. Here, we present a single-nucleus RNA-sequencing dataset describing the transcriptional responses of cells in mouse visual cortex to sensory deprivation or sensory stimulation during a developmental window when visual input is necessary for circuit refinement. We sequenced 118,529 individual nuclei across sixteen neuronal and non-neuronal cortical cell types isolated from control, sensory deprived, and sensory stimulated mice, identifying 1,268 unique sensory-induced genes within the developing brain. To demonstrate the utility of this resource, we compared the architecture and ontology of sensory-induced gene programs between cell types, annotated transcriptional induction and repression events based upon RNA velocity, and discovered Neurexin and Neuregulin signaling networks that underlie cell-cell interactions via CellChat. We find that excitatory neurons, especially layer 2/3 pyramidal neurons, are highly sensitive to sensory stimulation, and that the sensory-induced genes in these cells are poised to strengthen synapse-to-nucleus crosstalk by heightening protein serine/threonine kinase activity. Altogether, we expect this dataset to significantly broaden our understanding of the molecular mechanisms through which sensory experience shapes neural circuit wiring in the developing brain.

neuroscience↗

bioRxiv2025

Behavior choices amongst grooming, feeding, and courting in Drosophila show contextual flexibility, not an absolute hierarchy of needs

To determine the algorithmic rules and neural circuits controlling selection amongst competing behaviors, we established assays where adult Drosophila melanogaster choose between grooming and feeding, grooming and courting, or feeding and courting. We find that there is not an absolute hierarchy: while flies typically perform grooming first, they can choose to feed if sufficiently starved, or court if an appropriate female is available. Flies alternate between competing behaviors, performing short bouts of each action rather than completely satisfying one drive before transitioning to another. While we did not do an exhaustive screen, from the candidates we examined, we did not find evidence for a specific genetic or neuronal locus that affects all decisions. We did identify genetic background effects, suggesting that multiple genes may contribute to decision-making priorities. Our results add to a growing body of work on decision-making in Drosophila and provide a foundation for future investigation of the exact neural circuits required to achieve appropriate choices. Summary StatementFlies alternate between competing behaviors. The choice amongst positive actions depends on context and relative drive levels. No central decision-making locus was identified.

animal behavior and cognition↗

bioRxiv2023

Driver lines for studying associative learning in Drosophila

AbstractThe mushroom body (MB) is the center for associative learning in insects. In Drosophila, intersectional split-GAL4 drivers and electron microscopy (EM) connectomes have laid the foundation for precise interrogation of the MB neural circuits. However, investigation of many cell types upstream and downstream of the MB has been hindered due to lack of specific driver lines. Here we describe a new collection of over 800 split-GAL4 and split-LexA drivers that cover approximately 300 cell types, including sugar sensory neurons, putative nociceptive ascending neurons, olfactory and thermo-/hygro-sensory projection neurons, interneurons connected with the MB-extrinsic neurons, and various other cell types. We characterized activation phenotypes for a subset of these lines and identified a sugar sensory neuron line most suitable for reward substitution. Leveraging the thousands of confocal microscopy images associated with the collection, we analyzed neuronal morphological stereotypy and discovered that one set of mushroom body output neurons, MBON08/MBON09, exhibits striking individuality and asymmetry across animals. In conjunction with the EM connectome maps, the driver lines reported here offer a powerful resource for functional dissection of neural circuits for associative learning in adult Drosophila.

neuroscience↗

bioRxiv2018

Spatial organization of projection neurons in the mouse auditory cortex identified by in situ barcode sequencing

Understanding neural circuits requires deciphering interactions among myriad cell types defined by spatial organization, connectivity, gene expression, and other properties. Resolving these cell types requires both single neuron resolution and high throughput, a challenging combination with conventional methods. Here we introduce BARseq, a multiplexed method based on RNA barcoding for mapping projections of thousands of spatially resolved neurons in a single brain, and relating those projections to other properties such as gene or Cre expression. Mapping the projections to 11 areas of 3579 neurons in mouse auditory cortex using BARseq confirmed the laminar organization of the three top classes (IT, PT-like and CT) of projection neurons. In depth analysis uncovered a novel projection type restricted almost exclusively to transcriptionally-defined subtypes of IT neurons. By bridging anatomical and transcriptomic approaches at cellular resolution with high throughput, BARseq can potentially uncover the organizing principles underlying the structure and formation of neural circuits.

neuroscience↗

bioRxiv2022

A low-cost device for cryoanesthesia of neonate rodents

Studying the development of neural circuits in rodent models requires surgical access to the neonatal brain. Since commercially available stereotaxic and anesthetic equipment is designed for use in adults, reliable targeting of brain structures in such young animals can be challenging. Hypothermic cooling (cryoanesthesia) has been used as a preferred anesthesia approach in neonates. This commonly involves submerging neonates in ice, an approach that is poorly controllable. We have developed an affordable, simple to construct device - CryoPup - that allows for fast and robust cryoanesthesia of rodent pups. CryoPup consists of a microcontroller controlling a Peltier element and a heat exchanger. It is capable of both cooling and heating, thereby also functioning as a heating pad during recovery. Importantly, it has been designed for size compatibility with common stereotaxic frames. We validate CryoPup in neonatal mice, demonstrating that it allows for rapid, reliable and safe cryoanesthesia and subsequent recovery. This open-source device will facilitate future studies into the development of neural circuits in the postnatal brain. Specifications table O_TBL View this table: org.highwire.dtl.DTLVardef@de1fdorg.highwire.dtl.DTLVardef@16fde69org.highwire.dtl.DTLVardef@172f48corg.highwire.dtl.DTLVardef@15454forg.highwire.dtl.DTLVardef@79676e_HPS_FORMAT_FIGEXP M_TBL C_TBL

neuroscience↗

bioRxiv2023

Imbalanced expression of clustered protocadherins in pre- and post-synaptic compartments of CA1 pyramidal cells during hippocampal development

Clustered protocadherins (cPcdhs) are candidates for the neural circuit formation; however, the localization of cPcdhs in pre- and post-synaptic compartments has not been well characterized. Here we examined the localization of cPcdh{gamma} proteins in the mouse hippocampal CA1 region using light and electron microscopy. From postnatal day 7 to 21, cPcdh{gamma} immunosignals were detected in approximately 40-60% of spines of pyramidal cells. SDS-digested freeze-fracture replica labelling revealed that cPcdh{gamma} immunolabeling was found in 50% of PSD 95-positive postsynaptic profiles but only in less than 10% of vGluT1-positive pre-synaptic terminals. Interestingly, cPcdh{gamma}-positive pre-synaptic terminal was exclusively accompanied by cPcdh{gamma}-positive postsynaptic counterpart. In addition, electrophysiological investigations revealed that the miniature excitatory postsynaptic current frequency in cPcdh{gamma} cKO mice was significantly higher than that in wild-type mice. These results suggest that cPcdh{gamma} proteins are unequally distributed in the pre- and post-synaptic membrane during neural circuit development and regulate the number of excitatory synapses.

neuroscience↗

bioRxiv2020

Larval zebrafish respond to the alarm pheromone Schreckstoff by immobility and a change in brain state

BackgroundDetection of predator cues changes the brain state in prey species and helps them avoid danger. Dysfunctionality in changing the central state appropriately in stressful situations is proposed to be an underlying cause of multiple psychiatric disorders in humans. MethodsHere, we investigate the dynamics of neural circuits mediating response to a threat, to characterize these states and to identify potential control networks. We use resonant scanning 2-photon microscopy for in vivo brain-wide imaging and custom designed behavioral assays for the study. ResultsWe first show that 5-7 day old zebrafish larvae react to an alarm pheromone (Schreckstoff) with reduced mobility. They subsequently display heightened vigilance, as evidenced by increased dark avoidance. Calcium imaging indicates that exposure to Schreckstoff elicits stimulus-locked activity in olfactory sensory neurons innervating a lateral glomerulus and in telencephalic regions including the putative medial amygdala and entopeduncular nucleus. Sustained activity outlasting the stimulus delivery was detected in regions regulating neuromodulator release, including the lateral habenula, posterior tuberculum, superior raphe, and locus coeruleus. ConclusionWe propose that these latter regions contribute to the network that defines the "threatened" state, while neurons with transient activity serve as the trigger. Our study highlights the utility of the zebrafish larval alarm response system to examine neural circuits during stress dependent brain state transitions and to discover potential therapeutic agents when such transitions are disrupted.

neuroscience↗

bioRxiv2022

Bell Jar: A Semi-Automated Registration and Cell Counting Tool for Mouse Neurohistology Analysis

To investigate the anatomical organization of neural circuits across the whole brain, it is essential to register the experimental brain tissues to a reference atlas accurately. This procedure is also a prerequisite to quantify the locations and numbers of cells of interest in specific regions. However, it remains challenging to do registration on experimental tissue due to the intrinsic variation among the specimens, tissue deformation introduced by histological processing, and the potential inconsistency in the judgment of the experimenter during manual annotation. Here, we introduce Bell Jar, a multi-platform analysis tool with semi-automated affine warping of atlas maps onto microscopic images of brain slices and machine learning-based cell detection. Bell Jars intuitive GUI and internal dependency management enable users of all skill levels to obtain accurate results without programming expertise. To compare the performance of Bell Jar with previously published methods1-4, we labeled neurons in the mouse visual cortex with either an engineered rabies virus or an adeno-associated virus (AAV) for neural circuit tracing5, and quantified Bell Jars performance at each step of the pipeline for image alignment, segmentation, and cell counting. We demonstrated that Bell Jars output is as reliable as manual counting by an expert; it is more accurate than currently available techniques even with noisy data and takes less time with fewer user interventions. Bell Jar is an easy-to-navigate application that provides a reproducible, automated analysis workflow to facilitate the precise mapping of histological images of the mouse brain to the reference atlas and the quantification of cellular signals it is trained to recognize.

neuroscience↗

bioRxiv2018

Mechanisms of selection for the control of action in Drosophila melanogaster

In the last few years several studies have investigated the neural mechanisms underlying spatial orientation in Drosophila melanogaster. Convergent results suggest that this mechanism is associated with specific neural circuits located within the Central Complex (CC). Furthermore such circuits appear to be associated with visual attention, specifically with selective attention processes implicated in the control of action. Our aim was to understand how wild-type flies react to the abrupt appearance of a visual distractor during an ongoing locomotor action. Thus, we adapted the well-known Buridan paradigm, used to study walking behaviour in flies, so we could specifically address the mechanisms involved in action selection. We found that flies tended to react in one of two ways when confronted with a visual distractor during ongoing locomotion. Flies either: (i) committed to a new path situated midway between the original target and the distractor, consistent with a novelty effect; or (ii) remained on the original trajectory with a slight deviation in direction of the distractor. We believe that these results provide the first indication of how flies react, from the motor point of view, in a bi-stable context requiring the presence of selection-for-action mechanisms. Some considerations on the neural circuits underlying such behavioural responses are advanced.

animal behavior and cognition↗

bioRxiv2018

Expression of the Eight GABAA Receptor α Subunits in the Developing Zebrafish Central Nervous System

GABA is a robust regulator of both developing and mature neural networks. It exerts many of its effects through GABAA receptors, which are heteropentamers assembled from a large array of subunits encoded by distinct genes. In mammals, there are 19 different GABAA subunit types, which are divided into the , {beta}, {gamma}, {delta}, {varepsilon}, {pi}, {theta} and {rho} subfamilies. The immense diversity of GABAA receptors is not fully understood. However, it is known that specific isoforms, with their distinct biophysical properties and expression profiles, tune responses to GABA. Although larval zebrafish are well-established as a model system for neural circuit analysis, little is known about GABAA receptors diversity and expression in this system. Here, using database analysis, we show that the zebrafish genome contains at least 23 subunits. All but the mammalian {theta} and {varepsilon} subunits have at least one zebrafish ortholog, while five mammalian GABAA subunits have two zebrafish orthologs. Zebrafish contain one subunit, {beta}4, which does not have a clear mammalian ortholog. Similar to mammalian GABAA receptors, the zebrafish subfamily is the largest and most diverse of the subfamilies. In zebrafish there are eight subunits, and RNA in situ hybridization across early zebrafish development revealed that they demonstrate distinct patterns of expression in the brain, spinal cord, and retina. Some subunits were very broadly distributed, whereas others were restricted to small populations of cells. Subunit-specific expression patterns were similar between zebrafish, frogs and rodents, which suggests that the roles of different GABAA receptor isoforms are largely conserved among vertebrates. This study provides a platform to examine isoform specific roles of GABAA receptors within zebrafish neural circuits and it highlights the potential of this system to better understand the remarkable heterogeneity of GABAA receptors.

neuroscience↗