Andreas T Schaefer

• Professor at University College London

A common view of sensory processing is as probabilistic inference of latent causes from receptor activations. Standard approaches often assume these causes are a priori independent, yet real-world generative factors are typically correlated. Representing such structured priors in neural systems poses architectural challenges, particularly when dire...

Rodents rely on olfaction to navigate complex environments, particularly where visual cues are limited. Yet how they estimate the distance to an odour source remains unclear. The spatiotemporal dynamics of natural odour plumes, shaped by airflow turbulence, offer valuable cues for locating odour sources. Here, we show that mice can discriminate odo...

Information is routed between brain areas via parallel streams. Neurons may share common inputs yet convey distinct information to different downstream targets. Here, we leverage the anatomical organisation of the mouse olfactory bulb (OB), where dozens of projection neurons (mitral and tufted cells, M/TCs) affiliate with a single input unit, a glo...

Neuronal circuit reconstruction from X-ray holographic nanotomography (XNH) images of neuronal tissue requires overcoming limits in acquisition speed, image quality, and sample size. To fully exploit the higher brilliance of the European Synchrotron’s upgraded source, advances in endstation instrumentation and adapted data collection strategies are...

A core organizing principle of the vertebrate brain is its symmetry along multiple axes. However, the structure of these axes, and the precision with which neurons, circuit modules, and brain regions align to them, remain poorly understood. Here, we used 3D spatial transcriptomics to reconstruct the anatomical and molecular organization of the mous...

Coherent X-ray microscopy is emerging as a transformative technology for neuronal imaging, with the potential to offer a scalable solution for reconstruction of neural circuits in millimeter sized tissue volumes. Specifically, X-ray holographic nanotomography (XNH) brings together outstanding capabilities in terms of contrast, spatial resolution an...

Odours released by objects in natural environments can contain information about their spatial locations. In particular, the correlation of odour concentration timeseries produced by two spatially separated sources contains information about the distance between the sources. For example, mice are able to distinguish correlated and anti-correlated o...

Odors are transported by seemingly chaotic plumes, whose spatiotemporal structure contains rich information about space, with olfaction serving as a gateway for obtaining and processing this spatial information. Beyond tracking odors, olfaction provides localization and chemical communication cues for detecting conspecifics and predators, and linki...

Animals have evolved to rapidly detect and recognize brief and intermittent encounters with odor packages, exhibiting recognition capabilities within milliseconds. Artificial olfaction has faced challenges in achieving comparable results—existing solutions are either slow; or bulky, expensive, and power-intensive—limiting applicability in real-worl...

Animals have evolved to rapidly detect and recognise brief and intermittent encounters with odour packages, exhibiting recognition capabilities within milliseconds. Artificial olfaction has faced challenges in achieving comparable results -- existing solutions are either slow; or bulky, expensive, and power-intensive -- limiting applicability in re...

Active sampling in the olfactory domain is an important aspect of mouse behaviour, and there is increasing evidence that respiration-entrained neural activity outside of the olfactory system sets an important global brain rhythm. It is therefore important to accurately measure breathing during natural behaviours. We develop a new approach to do thi...

The sensory world is highly dynamic, and the temporal structure of stimuli contains rich information about the environment. Odour plumes are shaped by complex airflow that imprint information about the nature and spatial organisation of the olfactory environment onto their temporal dynamics. Whilst insects and mammals alike can discern high-frequen...

Spike timing-based representations of sensory information depend on embedded dynamical frameworks within neuronal networks that establish the rules of local computation and interareal communication. Here, we investigated the dynamical properties of olfactory bulb circuitry in mice of both sexes using microelectrode array recordings from slice and i...

Odours released by objects in natural environments can contain information about their spatial locations. In particular, the correlation of odour concentration fields produced by two spatially separated sources contains information about the distance between the sources. Mice are able to distinguish correlated and anti-correlated odour fluctuations...

Wiring diagrams of neural circuits are of central importance in delineating mechanisms of computation in the brain (Lichtman and Sanes, 2008; Litwin-Kumar and Turaga, 2019). To generate these diagrams, the individual parts of neurons - axons, dendrites and synapses - must be densely identified in 3-dimensional volumes of neuronal tissue. This is ty...

Active sampling in the olfactory domain is an important aspect of mouse behaviour. Numerous methods are being used to measure active sampling behaviour, yet reliable observation of respiration in untethered, freely moving animals is challenging. So far, methods for measuring this have largely been restricted to head-fixed sniff monitoring, which ma...

Correlative multimodal imaging is a useful approach to investigate complex structural relations in life sciences across multiple scales. For these experiments, sample preparation workflows that are compatible with multiple imaging techniques must be established. In one such implementation, a fluorescently labeled region of interest in a biological...

Correlative multimodal imaging is a useful approach to investigate complex structural relations in life sciences across multiple scales. For these experiments, sample preparation workflows that are compatible with multiple imaging techniques must be established. In one such implementation, a fluorescently-labelled region of interest in a biological...

Cells with latent stem ability can contribute to mammalian tissue regeneration after damage. Whether the central nervous system (CNS) harbors such cells remains controversial. Here, we report that DNGR-1 lineage tracing in mice identifies an ependymal cell subset, wherein resides latent regenerative potential. We demonstrate that DNGR-1-lineage-tra...

Integrating physiology with structural insights of the same neuronal circuit provides a unique approach to understanding how the mammalian brain computes information. However, combining the techniques that provide both streams of data represents an experimental challenge. When studying glomerular column circuits in the mouse olfactory bulb, this ap...

Rigorously quantifying perceptual similarity is essential to link sensory stimuli to neural activity and to define the dimensionality of perceptual space, which is challenging for the chemical senses in particular. Nakayama, Gerkin, and Rinberg present an efficient delayed match-to-sample behavioral paradigm that promises to provide a metric for od...

During wakefulness, the VTA represents the valence of experiences and mediates affective response to the outside world. Recent work revealed that two major VTA populations – dopamine and GABA neurons – are highly active during REM sleep, and less active during NREM sleep. Using long-term cell type and brain state-specific recordings, machine learni...

Odours are transported by turbulent air currents, creating complex temporal fluctuations in odour concentration that provide a potentially informative stimulus dimension. Recently, we have shown that mice are able to discriminate odour stimuli based on their temporal structure, indicating that information contained in the temporal structure of odou...

Objective. Extracellular microelectrode techniques are the most widely used approach to interrogate neuronal populations. However, regardless of the manufacturing method used, damage to the vasculature and circuit function during probe insertion remains a concern. This issue can be mitigated by minimising the footprint of the probe used. Reducing t...

Integrating physiology with structural insights of the same neuronal circuit provides a unique approach to understanding how the mammalian brain computes information. However, combining the techniques that provide both streams of data represents an experimental challenge. When studying glomerular column circuits in the mouse olfactory bulb, this ap...

Sensory processing is hard because the variables of interest are encoded in spike trains in a relatively complex way. A major goal in studies of sensory processing is to understand how the brain extracts those variables. Here we revisit a common encoding model in which variables are encoded linearly. Although there are typically more variables than...

Projection neurons (PNs) in the mammalian olfactory bulb (OB) receive input from the nose and project to diverse cortical and subcortical areas. Morphological and physiological studies have highlighted functional heterogeneity, yet no molecular markers have been described that delineate PN subtypes. Here, we used viral injections into olfactory cor...

Sensory processing is hard because the variables of interest are encoded in spike trains in a relatively complex way. A major goal in studies of sensory processing is to understand how the brain extracts those variables. Here we revisit a common encoding model in which variables are encoded linearly. Although there are typically more variables than...

Odours are transported in turbulent plumes, which result in rapid concentration fluctuations1,2 that contain rich information about the olfactory scenery, such as the composition and location of an odour source2–4. However, it is unclear whether the mammalian olfactory system can use the underlying temporal structure to extract information about th...

The sense of smell is an essential modality for many species, in particular nocturnal and crepuscular mammals, to gather information about their environment. Olfactory cues provide information over a large range of distances, allowing behaviours ranging from simple detection and recognition of objects, to tracking trails and navigating using odour...

Attributing in vivo neurophysiology to the brains' ultrastructure requires a large field of view containing contextual anatomy. Electron microscopy (EM) is the gold standard technique to identify ultrastructure, yet acquiring volumes containing full mammalian neural circuits is challenging and time consuming using EM. Here, we show that synchrotron...

Projection neurons (PNs) in the mammalian olfactory bulb (OB) receive direct input from the nose and project to diverse cortical and subcortical areas. Morphological and physiological studies have highlighted functional heterogeneity, yet no molecular markers have been described that delineate PN subtypes. Here, we used viral injections into olfact...

Odours are transported by turbulent air currents, creating complex temporal fluctuations in odour concentration. Recently, we have shown that mice can discriminate odour stimuli based on their temporal structure, indicating that information present in the temporal structure of odour plumes may be extracted by the mouse olfactory system. Here using...

Odours are transported by turbulent air currents, creating complex temporal fluctuations in odour concentration. Recently, we have shown that mice can discriminate odour stimuli based on their temporal structure, indicating that information present in the temporal structure of odour plumes may be extracted by the mouse olfactory system. Here using...

Mammalian brains consist of 10s of millions to 100s of billions of neurons operating at millisecond time scales, of which current recording techniques only capture a tiny fraction. Recording techniques capable of sampling neural activity at high spatiotemporal resolution have been difficult to scale. The most intensively studied mammalian neuronal...

For sensory systems of the brain, the dynamics of an animal’s own sampling behavior has a direct consequence on ensuing computations. This is particularly the case for mammalian olfaction, where a rhythmic flow of air over the nasal epithelium entrains activity in olfactory system neurons in a phenomenon known as sniff-locking. Parameters of sniffi...

Multi-channel electrical recordings of neural activity in the brain is an increasingly powerful method revealing new aspects of neural communication, computation, and prosthetics. However, while planar silicon-based CMOS devices in conventional electronics scale rapidly, neural interface devices have not kept pace. Here, we present a new strategy t...

Targeted electroporation by using glass microelectrodes is a popular and versatile tool allowing for easy manipulation of single cells and cell ensembles in living tissue. Because of the highly focal distribution of the electric field, however, the range of reversible electroporation without causing irreversible damage is tight—especially when aimi...

This article reviews the contributions of the English neurophysiologist, Charles Scott Sherrington [1857-1952], and his Australian PhD trainee and collaborator, John Carew Eccles [1903-1997], to the concept of central inhibition in the spinal cord and brain. Both were awarded Nobel Prizes; Sherrington in 1932 for "discoveries regarding the function...

High signal-to-noise, scalable and minimally invasive recording and stimulation of the nervous system in intact animals is of fundamental importance to advance the understanding of brain function. Extracellular electrodes are among the most powerful tools capable of interfacing with large neuronal populations. Neuronal tissue damage remains a major...

Multiple-channel count neural recordings of brain activity are a powerful technique that is increasingly uncovering new aspects of neural communication, computation, and prosthetic interfaces. However, while silicon CMOS devices continue to scale rapidly in number and power in planar geometries, this scaling has not been followed for large-scale ma...

Odours are transported in turbulent plumes resulting locally in highly fluctuating odour concentration (Celani et al., 2014; Murlis et al., 1992; Mylne and Mason, 1991; Shraiman and Siggia, 2000). Yet, whether mammals can make use of the ensuing temporal structure (Celani et al., 2014; Crimaldi and Koseff, 2001; Murlis et al., 1992; Mylne and Mason...

Mammalian brains consist of 10s of millions to 100s of billions of neurons operating at millisecond time scales, of which current recording techniques only capture a tiny fraction. Recording techniques capable of sampling neural activity at such temporal resolution have been difficult to scale: The most intensively studied mammalian neuronal networ...

Operant conditioning is a crucial tool in neuroscience research for probing brain function. While molecular, anatomical and even physiological techniques have seen radical increases in throughput, efficiency, and reproducibility in recent years, behavioural tools have somewhat lagged behind. Here we present a fully automated, high-throughput system...

Excitotoxic olfactory bulb lesions. MicroCT images from mice injected with varying amounts of NMDA into the olfactory bulb (Sham: 0ng, S: 303.6ng, M: 607.2ng, L: 1214ng, XL 1669.8ng, XXL: 2125ng). Images are reconstructed coronal sections from a whole mouse head, starting at 0mm from bregma, to 1–1.3mm anterior from bregma (roughly the olfactory bu...

Differences in performance for AutonoMouse cohort sizes. (a) Average trials per day for each animal plotted against the group size (number of animals) in which the animal performed. There is a significant negative correlation between group size and daily trials performed for each animal. (b) Fraction of trials performed each hour analysed as in Fig...

Performance is correlated with daily trials performed, but not with average stretch length of those trials (a) Mean performance of all lesion study animals (n = 29) against average daily trials performed. Average daily trials is significantly positively correlated with mean performance (R = 0.5329, p = 0.0029). (b) Mean performance of the same anim...

Quality of learning during olfactory discrimination in AutonoMouse related to time taken to perform trials. (a1) Number of hours taken to perform a target number of trials (1st 500) during initial odour pair learning vs. novel odour pair learning (n = 29). Hours to target are significantly correlated across the two task types (R = 0.84, p = 1.22x10...

Adapting neural representation to rapidly changing behavioural demands is a key challenge for the nervous system. Here, we demonstrate that the output of the primary olfactory area of the mouse, the olfactory bulb, is already a target of dynamic and reproducible modulation. The modulation depends on the stimulus tuning of a given neuron, making olf...

Adapting neural representation to rapidly changing behavioural demands is a key challenge for the nervous system. Here, we demonstrate that the output of the primary olfactory area, the mouse olfactory bulb, is already a target of dynamic and reproducible modulation. The modulation depends on the stimulus tuning of a given neuron, making olfactory...

In awake mice, sniffing behavior is subject to complex contextual modulation. It has been hypothesized that variance in inhalation dynamics alters odor concentration profiles in the naris despite a constant environmental concentration. Using whole-cell recordings in the olfactory bulb of awake mice, we directly demonstrate that rapid sniffing mimic...

Juxtaglomerular cells (JGCs) of the olfactory bulb (OB) glomerular layer (GL) play a fundamental role in olfactory information processing. Their variability in morphology, physiology, and connectivity suggests distinct functions. The quantitative understanding of populationwise morphological and physiological properties and a comprehensive classifi...

The olfactory bulb (OB) is the first site of synaptic odor information processing, yet a wealth of contextual and learned information has been described in its activity. To investigate the mechanistic basis of contextual modulation, we use whole-cell recordings to measure odor responses across rapid learning episodes in identified mitral/tufted cel...

The olfactory bulb (OB) is the first site of synaptic odor information processing, yet a wealth of contextual and learned information has been described in its activity. To investigate the mechanistic basis of contextual modulation, we use whole-cell recordings to measure odor responses across rapid learning episodes in identified mitral/tufted cel...

Operant conditioning is a crucial tool in neuroscience research for probing brain function. While molecular, anatomical and even physiological techniques have seen radical increases in throughput, efficiency, and reproducibility in recent years, behavioural tools have seen much less of an improvement. Here we present a fully automated, high-through...

Nanodiamonds have many attractive properties that make them suitable for a range of biological applications, but their practical use has been limited because nanodiamond conjugates tend to aggregate in solution during or after functionalisation. Here we demonstrate the production of DNA-detonation nanodiamond (DNA-DND) conjugates with high dispersi...

Dense microcircuit reconstruction techniques have begun to provide ultrafine insight into the architecture of small-scale networks. However, identifying the totality of cells belonging to such neuronal modules, the "inputs" and "outputs," remains a major challenge. Here, we present the development of nanoengineered electroporation microelectrodes (...

For stable perception of odor intensity, there must exist a neural correlate that is invariant across other parameters, such as the highly variable sniff cycle. Previous hypotheses suggest that variance in inhalation dynamics alters odor concentration profiles in the naris despite a constant environmental concentration. Using whole cell recordings...

The olfactory bulb (OB) is the very first site of odor information processing, yet a wealth of contextual and learned information has been described in its activity. To investigate the mechanistic basis of contextual modulation, we use whole-cell recordings to measure odor responses across rapid (<30 min) learning episodes in identified mitral/tuft...

Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched ‘‘The Science Bridge’’ initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.

Spike timing-based representations of sensory information depend on embedded dynamical frameworks within neuronal networks that establish the rules of local computation and interareal communication. Here, we investigated the dynamical properties of olfactory bulb circuitry in mice of both sexes using microelectrode array recordings from slice and i...

Representations in excitatory neurons generally narrow as they are refined. Odor representations in interneurons, however, broaden with maturation and learning, as connections between interneurons and projection neurons expand.

Nanoscale devices have been proposed as tools for measuring and controlling intracellular activity by providing electrical and/or chemical access to the cytosol. Unfortunately, nanostructures with diameters of 50-500 nm do not readily penetrate the cell membrane, and rationally optimizing nanoprobes for cell penetration requires real-time character...

The raphe nuclei provide serotonergic innervation widely in the brain, thought to mediate a variety of neuromodulatory effects. The mammalian olfactory bulb (OB) is a prominent recipient of serotonergic fibres, particularly in the glomerular layer (GL) where they are thought to gate the incoming signals from the olfactory nerve. The dorsal raphe nu...

How wakefulness shapes neural activity is a topic of intense discussion. In the awake olfactory bulb, high activity with weak sensory-evoked responses has been reported in mitral/tufted cells (M/TCs). Using blind whole-cell recordings, we found 33% of M/TCs to be 'silent', yet still show strong sensory responses, with weak or inhibitory responses i...

Circuits in the brain possess the ability to orchestrate activities on different timescales, but the manner in which distinct circuits interact to sculpt diverse rhythms remains unresolved. The olfactory bulb is a classic example of a place in which slow theta and fast gamma rhythms coexist. Furthermore, inhibitory interneurons that are generally i...

Neurons integrate synaptic inputs across time and space, a process that determines the transformation of input signals into action potential output. This article explores how synaptic integration contributes to the richness of sensory signalling in the cerebellar and cerebral cortices. Whether a neuron receives a few or a few thousand discrete inpu...

This article reviews the contributions of Ivan Michailovich Sechenov [1829-1905] to the neurophysiological concept of central inhibition. He first studied this concept in the frog and on himself. Later his trainees extended the study of central inhibition to other mammalian species. Outside his own country, Sechenov is better known for his prescien...

Lesion experiments suggest that odour input to the olfactory bulb contains significant redundant signal such that rodents can discern odours using minimal stimulus-related information. Here we investigate the dependence of odour-quality perception on the integrity of glomerular activity by comparing odour-evoked activity maps before and after epith...

Supplementary Figures S1-S6 and Supplementary Methods

Direct electrical recording of the neuronal transmembrane potential has been crucial to our understanding of the biophysical mechanisms subserving neuronal computation. Existing intracellular recording techniques, however, limit the accuracy and duration of such measurements by changing intracellular biochemistry and/or by damaging the plasma membr...

SCINE fabrication scheme. This schematic shows the process of making SCINEs, as described in the Methods section. (TIF)

SCINE signal loss. A This brief SCINE recording (red) and whole-cell recording (black) are annotated to highlight three time periods before membrane penetration (1), immediately after membrane penetration (2), and when the SCINE signal is diminishing (3). Throughout the entire duration, the whole-cell recording appears undisturbed (black). The time...

Untreated tungsten nanoelectrode. A Untreated SCINES considerably deform the neuronal plasma membrane prior to penetration. B Recording from an untreated SCINE (red). The recording begins after the SCINE has already been pushed deeply into the neuronal cell body as schematized in A. The neuron is firing action potentials, which are evoked by somati...

SCINE recording of multiple APs. SCINE (red) and whole-cell recording (black) measurements of current-evoked action potentials. Traces are single, unaveraged traces. (TIF)

Unsuccessful SCINE penetration. SCINEs do not yet work as reliably as sharp microelectrodes or patch pipettes; non-destructive membrane penetration occurs only in a minority of cases. A This double-recording typifies an unsuccessful attempt at SCINE recording (red). The whole-cell recording (black) shows that the cell input resistance drops and the...

Spike waveforms (single trials) from SCINE and whole-cell recording. SCINE (red) and whole-cell recording (black) measurements of the same action potential are overlaid with each other to show the relative filtering properties of the two electrodes. Spikes are displayed for each of the cells shown in Figure 4. Traces are single, unaveraged traces....

Rhythmic neural activity is a hallmark of brain function, used ubiquitously to structure neural information. In mammalian olfaction, repetitive sniffing sets the principal rhythm but little is known about its role in sensory coding. Here, we show that mitral and tufted cells, the two main classes of olfactory bulb projection neurons, tightly lock t...

Electrophysiological and population imaging data in rodents show that olfactory bulb (OB) activity is profoundly modulated by the odor sampling process while behavioral experiments indicate that odor discrimination can occur within a single sniff. This paper addresses the question of whether action potential (AP) latencies occurring across the mitr...

Genetics' demand for increased throughput is driving automatization of behavior analysis far beyond experimental workhorses like circadian monitors and the operant conditioning box. However, the new automation is not just faster: it is also allowing new kinds of experiments, many of which erase the boundaries of the traditional neuroscience discipl...

How sensory stimuli are processed by neural networks is a key question of neuroscience. Olfactory conditioning experiments in mice demonstrate that odour processing is fast and stimulus-dependent. Selective genetic perturbation of the inhibitory circuitry in the first relay station of olfactory processing, the olfactory bulb, altered such discrimin...