Biology subjects

Axel, R.

Publications and source records attributed to Axel, R..

17 recordsLinked to original sources

bioRxiv2026

A new neural code for position: generalizable spatial maps in mouse medial frontal cortex

Navigation requires the brain to encode spatial relationships that support extrapolation from explored to unexplored regions of space. We identified a novel neural code for space in the mouse medial frontal cortex (mFC) that is well suited for this form of spatial generalization. Using calcium imaging of excitatory neurons in mFC, hippocampus (dorsal CA1), and lateroventral orbitofrontal cortex (lvOFC) as mice explored a square arena with landmarks, we found that mFC activity supports extrapolation. Linear regression of the animal's x or y coordinates trained in one region of the arena generalized to a completely different region. This property was observed in mFC but not in dCA1 or lvOFC. A model in which neurons encode the squared distance from the animal to multiple landmarks explains several properties of the geometry of the mFC representation, including extrapolation. The neural map that we observed in the frontal cortex may provide a basis for vector computation in navigation and complex route planning.

neuroscience↗

bioRxiv2026

Generation of a transgenic cephalopod

Coleoid cephalopods (cuttlefish, octopus, and squid) are marine mollusks with elaborate nervous systems that support a diverse repertoire of complex behaviors. These include the neural control of the color, pattern, and texture of the skin, facilitating both adaptive camouflage and innate patterning that may reflect internal state. The development of transgenic cephalopods expressing fluorescent proteins, optogenetic actuators, and reporters of neural activity would contribute a new and important technology to cephalopod biology. The generation of transgenic cephalopods, however, has remained a major challenge. Here, we report the development of stable transgenic dwarf cuttlefish (Ascarosepion bandense) expressing ubiquitous nuclear-localized mScarlet, a red fluorescent protein. We evaluated multiple strategies for transgenesis, and established cuttlefish lines using both CRISPR and the transposons Sleeping Beauty and Minos. The stable expression of transgenes enabled live imaging of cell dynamics during embryonic development. The Minos transposon emerged as the most efficient transgenesis strategy and is adaptable to promoters and transgenes of choice. These strategies now enable the generation of diverse genetic tools for mechanistic studies of cephalopod biology.

genetics↗

bioRxiv2025

Experience-dependent reorganization of inhibitory neuron synaptic connectivity

Organisms continually tune their perceptual systems to the features they encounter in their environment1-3. We have studied how ongoing experience reorganizes the synaptic connectivity of neurons in the olfactory (piriform) cortex of the mouse. We developed an approach to measure synaptic connectivity in vivo, training a deep convolutional network to reliably identify monosynaptic connections from the spike-time cross-correlograms of 4.4 million single-unit pairs. This revealed that excitatory piriform neurons with similar odor tuning are more likely to be connected. We asked whether experience enhances this like-to-like connectivity but found that it was unaffected by odor exposure. Experience did, however, alter the logic of interneuron connectivity. Following repeated encounters with a set of odorants, inhibitory neurons that responded differentially to these stimuli exhibited a high degree of both incoming and outgoing synaptic connections within the cortical network. This reorganization depended only on the odor tuning of the inhibitory interneuron and not on the tuning of its pre- or postsynaptic partners. A computational model of this reorganized connectivity predicts that it increases the dimensionality of the entire networks responses to familiar stimuli, thereby enhancing their discriminability. We confirmed that this network-level property is present in physiological measurements, which showed increased dimensionality and separability of the evoked responses to familiar versus novel odorants. Thus, a simple, non-Hebbian reorganization of interneuron connectivity may selectively enhance an organisms discrimination of the features of its environment.

neuroscience↗

bioRxiv2023

Representations of information value in mouse orbitofrontal cortex during information seeking

Animals are motivated to seek information that does not influence reward outcomes, suggesting that information has intrinsic value. We have developed an odor-based information seeking task that reveals that mice choose to receive information even though it does not alter the reward outcome. Moreover, mice are willing to pay for information by sacrificing water reward, suggesting that information is of intrinsic value to a mouse. We used a microendoscope to reveal neural activity in orbitofrontal cortex (OFC) while mice learned the information seeking task. We observed the emergence of distinct populations of neurons responsive to odors predictive of information and odors predictive of water reward. A latent variable model recapitulated these different representations in the low-dimensional dynamics of OFC neuronal population activity. These data suggest that mice have evolved separate pathways to represent the intrinsic value of information and the extrinsic value of water reward. Thus, the desire to acquire knowledge is observed in mice, and the value of this information is represented in the OFC. The mouse now provides a facile experimental system to study the representation of the value of information, a higher cognitive variable.

neuroscience↗

bioRxiv2023

A rapid and bidirectional reporter of neural activity reveals neural correlates of social behaviors in Drosophila

Neural activity is modulated over different timescales encompassing sub-seconds to days reflecting changes in external environment, internal state, and behavior. Using Drosophila as a model, we have developed a rapid and bidirectional reporter that provides a robust cellular readout of recent neural activity. This reporter utilizes nuclear vs cytoplasmic distribution of CREB-regulated transcriptional coactivator, CRTC. Subcellular distribution of GFP-tagged CRTC (CRTC::GFP) bidirectionally changes on the order of minutes and reflects both increases and decreases in neural activity. We establish an automated machine-learning-based routine for efficient quantification of reporter signal. Using this reporter, we demonstrate acute mating- evoked activation of peptidergic neurons. We further investigate the functional role of the master courtship regulator gene, fruitless, and show that fruitless is necessary to ensure activation of male arousal neurons by female cues. Together, our results establish CRTC::GFP as a bidirectional reporter of recent neural activity suitable for examining neural correlates in behavioral contexts.

neuroscience↗

bioRxiv2023

Phased nanopore assembly with Shasta and modular graph phasing with GFAse

As a step towards simplifying and reducing the cost of haplotype resolved de novo assembly, we describe new methods for accurately phasing nanopore data with the Shasta genome assembler and a modular tool for extending phasing to the chromosome scale called GFAse. We test using new variants of Oxford Nanopore Technologies (ONT) PromethION sequencing, including those using proximity ligation and show that newer, higher accuracy ONT reads substantially improve assembly quality.

bioinformatics↗

bioRxiv2022

A brain atlas of the camouflaging dwarf cuttlefish, Sepia bandensis

The coleoid cephalopods (cuttlefish, octopus, and squid) are a group of soft-bodied marine mollusks that exhibit an array of interesting biological phenomena, including dynamic camouflage, complex social behaviors, prehensile regenerating arms, and large brains capable of learning, memory, and problem-solving [1-10]. The dwarf cuttlefish, Sepia bandensis, is a promising model cephalopod species due to its small size, substantial egg production, short generation time, and dynamic social and camouflage behaviors [11]. Cuttlefish dynamically camouflage to their surroundings by changing the color, pattern and texture of their skin. Camouflage is optically-driven, and is achieved by expanding and contracting hundreds of thousands of pigment-filled saccules (chromatophores) in the skin, which are controlled by motor neurons emanating from the brain. We generated a dwarf cuttlefish brain atlas using magnetic resonance imaging (MRI), deep learning, and histology, and we built an interactive web tool (cuttlebase.org) to host the data. Guided by observations in other cephalopods [12-20], we identified 32 brain lobes, including two large optic lobes (75% the total volume of the brain), chromatophore lobes whose motor neurons directly innervate the chromatophores of the color-changing skin, and a vertical lobe that has been implicated in learning and memory. This brain atlas provides a valuable tool for exploring the neural basis of cuttlefish behavior.

neuroscience↗

bioRxiv2021

Flygenvectors: The spatial and temporal structure of neural activity across the fly brain

What are the spatial and temporal scales of brainwide neuronal activity, and how do activities at different scales interact? We used SCAPE microscopy to image a large fraction of the central brain of adult Drosophila melanogaster with high spatiotemporal resolution while flies engaged in a variety of behaviors, including running, grooming and flailing. This revealed neural representations of behavior on multiple spatial and temporal scales. The activity of most neurons across the brain correlated (or, in some cases, anticorrelated) with running and flailing over timescales that ranged from seconds to almost a minute. Grooming elicited a much weaker global response. Although these behaviors accounted for a large fraction of neural activity, residual activity not directly correlated with behavior was high dimensional. Many dimensions of the residual activity reflect the activity of small clusters of spatially organized neurons that may correspond to genetically defined cell types. These clusters participate in the global dynamics, indicating that neural activity reflects a combination of local and broadly distributed components. This suggests that microcircuits with highly specified functions are provided with knowledge of the larger context in which they operate, conferring a useful balance of specificity and flexibility.

neuroscience↗

bioRxiv2021

Evolving the Olfactory System with Machine Learning

The convergent evolution of the fly and mouse olfactory system led us to ask whether the anatomic connectivity and functional logic of olfactory circuits would evolve in artificial neural networks trained to perform olfactory tasks. Artificial networks trained to classify odor identity recapitulate the connectivity inherent in the olfactory system. Input units are driven by a single receptor type, and units driven by the same receptor converge to form a glomerulus. Glomeruli exhibit sparse, unstructured connectivity to a larger, expansion layer of Kenyon cells. When trained to both classify odor identity and to impart innate valence onto odors, the network develops independent pathways for identity and valence classification. Thus, the defining features of fly and mouse olfactory systems also evolved in artificial neural networks trained to perform olfactory tasks. This implies that convergent evolution reflects an underlying logic rather than shared developmental principles.

neuroscience↗

bioRxiv2021

Decisions in an Innate Behavioral Sequence

Innate behaviors are comprised of ordered sequences of component actions that progress to satisfy drives. We have characterized the structure of egg-laying behavior in Drosophila in detail and observed that the sequence is not merely comprised of motor acts but also acts of sensory exploration that govern the transitions between component actions. We have identified a cluster of internal sensory neurons that provide information about the progression of the egg during ovipositor burrowing, a behavior necessary for the subterraneous deposition of the egg. These neurons impart sensory feedback that allows burrowing to continue to egg deposition or to abort in favor of further exploration. Diminished activity of these neurons upon completed egg expulsion may initiate the transition to the final phase of egg-laying, allowing the cycle to repeat. Sensory feedback therefore plays a critical role at decision points between transitions affording innate behaviors with an adaptive flexibility.

neuroscience↗

bioRxiv2020

Representational drift in primary olfactory cortex

Representations of the external world in sensory cortices may define the identity of a stimulus and should therefore vary little over the life of the organism. In the olfactory system the primary olfactory cortex, piriform, is thought to determine odor identity1-6. We have performed electrophysiological recordings of single units maintained over weeks to examine the stability of odor representations in the mouse piriform cortex. We observed that odor representations drift over time, such that the performance of a linear classifier trained on the first recording day approaches chance levels after 32 days. Daily exposure to the same odorant slows the rate of drift, but when exposure is halted that rate increases once again. Moreover, behavioral salience does not stabilize odor representations. Continuous drift poses the question of the role of piriform in odor identification. This instability may reflect the unstructured connectivity of piriform7-15 and may be a property of other unstructured cortices.

neuroscience↗

bioRxiv2020

Individual bitter-sensing neurons in Drosophila exhibit both ON and OFF responses that influence synaptic plasticity

The brain creates internal representations that translate sensory stimuli into appropriate behavior. Most studies of sensory processing focus on which subsets of neurons are activated by a stimulus, but the temporal features of the neural response are also important for behavior. In the taste system, the timing of peripheral sensory responses has rarely been examined. We investigated the temporal properties of taste responses in Drosophila melanogaster and discovered that different types of taste sensory neurons show striking differences in their response dynamics. Strong responses to stimulus onset (ON responses) and offset (OFF responses) were observed in bitter-sensing neurons in the labellum, whereas bitter neurons in the leg and other classes of labellar taste neurons showed only an ON response. Individual bitter labellar neurons generate both the ON and OFF responses through a cell-intrinsic mechanism that requires canonical bitter receptors. The bitter ON and OFF responses at the periphery are propagated to dopaminergic neurons that innervate the mushroom body and mediate aversive learning. When bitter is used as a reinforcement cue, the bitter ON and OFF responses can drive opposing types of synaptic plasticity and the effect of the OFF response dominates, likely due to the rapid and preferential habituation of the ON response. Together, these studies characterize novel features of neural responses in the taste system and reveal their importance for neural circuit function.

neuroscience↗

bioRxiv2019

Context-dependent decision making in a premotor circuit

Cognitive capacities afford contingent associations between sensory information and behavioral responses. We studied this problem using an olfactory delayed match to sample task whereby a sample odor specifies the association between a subsequent test odor and rewarding action. Multi-neuron recordings revealed representations of the sample and test odors in olfactory sensory and association cortex, which were sufficient to identify the test odor as match/non-match. Yet, inactivation of a downstream premotor area (ALM), but not orbitofrontal cortex, confined to the epoch preceding the test odor, led to gross impairment. Olfactory decisions that were not context dependent were unimpaired. Therefore, ALM may not receive the outcome of a match/non-match decision from upstream areas but contextual information--the identity of the sample--to establish the mapping between test odor and action. A novel population of pyramidal neurons in ALM layer 2 may mediate this process.

neuroscience↗

bioRxiv2019

Olfactory Landmarks and Path Integration Converge to Form a Cognitive Spatial Map

The convergence of internal path integration with sensory information from external landmarks generates a cognitive spatial map in the hippocampus. We have recorded the activity of cells in CA1 during a virtual navigation task to examine how mice represent, recognize and employ sparse olfactory landmarks to estimate their location. We observe that the presence of odor landmarks at multiple locations in a virtual environment greatly enriches the place cell representation and dramatically improves navigation. Presentation of the same odor at different locations generates distinct place cell representations, indicating that path integration can disambiguate two identical cues on the basis of location. The enhanced place cell representation at one cue location led to the formation of place cells at locations beyond that cue and, ultimately recognition of a second odor cue as a distinct landmark. This suggests an iterative mechanism for extending place cell representations into unknown territory. These results reveal how odor cues can serve as landmarks to guide navigation and suggest a model to explain how the convergence of landmarks and path integration participates in an iterative process that generates a cognitive spatial map.

neuroscience↗

bioRxiv2019

The Imposition of Value on Odor: Transient and Persistent Representations of Odor Value in Prefrontal Cortex

The representation of odor in olfactory cortex (piriform) is distributive and unstructured and can only be afforded behavioral significance upon learning. We performed 2-photon imaging to examine the representation of odors in piriform and in two downstream stations, the orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), as mice learned olfactory associations. In piriform we observed minor changes in neural activity unrelated to learning. In OFC, 30% of the neurons acquired robust responses to conditioned stimuli (CS+) after learning, and these responses were gated by context and internal state. The representation in OFC, however, diminished after learning and persistent representations of CS+ and CS- odors emerged in mPFC. Optogenetic silencing indicates that these two brain structures function sequentially to consolidate the learning of appetitive associations. These data demonstrate the transformation of a representation of odor identity in piriform into transient and persistent representations of value in the prefrontal cortex.

neuroscience↗

bioRxiv2018

Acetic acid activates distinct taste pathways in Drosophila to elicit opposing, state-dependent feeding responses

Taste circuits are genetically determined to elicit an innate appetitive or aversive response, ensuring that animals consume nutritious foods and avoid the ingestion of toxins. We have examined the response of the fruit fly Drosophila melanogaster to acetic acid, a tastant that can be a metabolic resource but can also be toxic to the fly. Our data reveal that flies accommodate these conflicting attributes of acetic acid by virtue of a hunger-dependent switch in their behavioral response to this stimulus. Fed flies show taste aversion to acetic acid, likely a response to its potential toxicity, whereas starved flies show a robust appetitive response that may reflect their overriding need for calories. These opposing responses are mediated by two different classes of taste neurons. Acetic acid activates both the sugar and bitter pathways, which have opposing effects on feeding behavior. Hunger shifts the response from aversion to attraction by enhancing the appetitive sugar pathway as well as suppressing the aversive bitter pathway. Thus a single tastant can drive opposing behaviors by activating distinct taste pathways modulated by internal state.

neuroscience↗

bioRxiv2017

A naturalistic assay for measuring behavioral responses to aversive stimuli at millisecond timescale

We have designed a Virtual Burrow Assay (VBA) to detect the behavioral responses of head-fixed mice to aversive stimuli. We demonstrate its suitability for measuring novelty detection as well as aversion to both conditioned and innately aversive cues. The VBA simulates a scenario in which a mouse, poised at the threshold of its burrow, evaluates whether to remain exposed to potential threats outside or to retreat inside an enclosure. When presented with aversive stimuli, mice exhibit a stereotyped retreat whose onset is determined by measuring the position of a moveable burrow. This withdrawal, which requires no training, is characterized by an abrupt transition that unfolds within milliseconds--a timescale similar to that of neuronal dynamics, permitting direct comparison between the two. The assay is compatible with standard electrophysiological and optical methods for measuring and perturbing neuronal activity.

neuroscience↗