Publications by authors named "Andreas T Schaefer"

43 Publications

Fast odour dynamics are encoded in the olfactory system and guide behaviour.

Nature 2021 May 5. Epub 2021 May 5.

Sensory Circuits and Neurotechnology Laboratory, The Francis Crick Institute, London, UK.

Odours are transported in turbulent plumes, which result in rapid concentration fluctuations that contain rich information about the olfactory scenery, such as the composition and location of an odour source. However, it is unclear whether the mammalian olfactory system can use the underlying temporal structure to extract information about the environment. Here we show that ten-millisecond odour pulse patterns produce distinct responses in olfactory receptor neurons. In operant conditioning experiments, mice discriminated temporal correlations of rapidly fluctuating odours at frequencies of up to 40 Hz. In imaging and electrophysiological recordings, such correlation information could be readily extracted from the activity of mitral and tufted cells-the output neurons of the olfactory bulb. Furthermore, temporal correlation of odour concentrations reliably predicted whether odorants emerged from the same or different sources in naturalistic environments with complex airflow. Experiments in which mice were trained on such tasks and probed using synthetic correlated stimuli at different frequencies suggest that mice can use the temporal structure of odours to extract information about space. Thus, the mammalian olfactory system has access to unexpectedly fast temporal features in odour stimuli. This endows animals with the capacity to overcome key behavioural challenges such as odour source separation, figure-ground segregation and odour localization by extracting information about space from temporal odour dynamics.
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http://dx.doi.org/10.1038/s41586-021-03514-2DOI Listing
May 2021

Spatial information from the odour environment in mammalian olfaction.

Cell Tissue Res 2021 Jan 30;383(1):473-483. Epub 2021 Jan 30.

Sensory Circuits and Neurotechnology Laboratory, The Francis Crick Institute, London, UK.

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 plumes from afar. In this review, we discuss the features of the natural olfactory environment and provide a brief overview of how odour information can be sampled and might be represented and processed by the mammalian olfactory system. Finally, we discuss recent behavioural approaches that address how mammals extract spatial information from the environment in three different contexts: odour trail tracking, odour plume tracking and, more general, olfactory-guided navigation. Recent technological developments have seen the spatiotemporal aspect of mammalian olfaction gain significant attention, and we discuss both the promising aspects of rapidly developing paradigms and stimulus control technologies as well as their limitations. We conclude that, while still in its beginnings, research on the odour environment offers an entry point into understanding the mechanisms how mammals extract information about space.
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http://dx.doi.org/10.1007/s00441-020-03395-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872987PMC
January 2021

CHIME: CMOS-Hosted Microelectrodes for Massively Scalable Neuronal Recordings.

Front Neurosci 2020 11;14:834. Epub 2020 Aug 11.

Neurophysiology of Behaviour Laboratory, Francis Crick Institute, London, United Kingdom.

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 networks, such as the neocortex, show a layered architecture, where the optimal recording technology samples densely over large areas. However, the need for application-specific designs as well as the mismatch between the three-dimensional architecture of the brain and largely two-dimensional microfabrication techniques profoundly limits both neurophysiological research and neural prosthetics. Here, we discuss a novel strategy for scalable neuronal recording by combining bundles of glass-ensheathed microwires with large-scale amplifier arrays derived from high-density CMOS MEA systems or high-speed infrared cameras. High signal-to-noise ratio (<25 μV RMS noise floor, SNR up to 25) is achieved due to the high conductivity of core metals in glass-ensheathed microwires allowing for ultrathin metal cores (down to <1 μm) and negligible stray capacitance. Multi-step electrochemical modification of the tip enables ultra-low access impedance with minimal geometric area, which is largely independent of the core diameter. We show that the microwire size can be reduced to virtually eliminate damage to the blood-brain-barrier upon insertion and we demonstrate that microwire arrays can stably record single-unit activity. Combining microwire bundles and CMOS arrays allows for a highly scalable neuronal recording approach, linking the progress in electrical neuronal recordings to the rapid progress in silicon microfabrication. The modular design of the system allows for custom arrangement of recording sites. Our approach of employing bundles of minimally invasive, highly insulated and functionalized microwires to extend a two-dimensional CMOS architecture into the 3rd dimension can be translated to other CMOS arrays, such as electrical stimulation devices.
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http://dx.doi.org/10.3389/fnins.2020.00834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432274PMC
August 2020

Respiration-Locking of Olfactory Receptor and Projection Neurons in the Mouse Olfactory Bulb and Its Modulation by Brain State.

Front Cell Neurosci 2020 16;14:220. Epub 2020 Jul 16.

Sensory and Behavioural Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.

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 sniffing can, however, change drastically with brain states. Coupled to the fact that different observation methods have different kinetics, consensus on the sniff-locking properties of neurons is lacking. To address this, we investigated the sniff-related activity of olfactory sensory neurons (OSNs), as well as the principal neurons of the olfactory bulb (OB), using 2-photon calcium imaging and intracellular whole-cell patch-clamp recordings , both in anesthetized and awake mice. Our results indicate that OSNs and OB output neurons lock robustly to the sniff rhythm, but with a slight temporal shift between behavioral states. We also observed a slight delay between methods. Further, the divergent sniff-locking by tufted cells (TCs) and mitral cells (MCs) in the absence of odor can be used to determine the cell type reliably using a simple linear classifier. Using this classification on datasets where morphological identification is unavailable, we find that MCs use a wider range of temporal shifts to encode odors than previously thought, while TCs have a constrained timing of activation due to an early-onset hyperpolarization. We conclude that the sniff rhythm serves as a fundamental rhythm but its impact on odor encoding depends on cell type, and this difference is accentuated in awake mice.
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http://dx.doi.org/10.3389/fncel.2020.00220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378796PMC
July 2020

Massively parallel microwire arrays integrated with CMOS chips for neural recording.

Sci Adv 2020 03 20;6(12):eaay2789. Epub 2020 Mar 20.

Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA.

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 to interface silicon-based chips with three-dimensional microwire arrays, providing the link between rapidly-developing electronics and high density neural interfaces. The system consists of a bundle of microwires mated to large-scale microelectrode arrays, such as camera chips. This system has excellent recording performance, demonstrated via single unit and local-field potential recordings in isolated retina and in the motor cortex or striatum of awake moving mice. The modular design enables a variety of microwire types and sizes to be integrated with different types of pixel arrays, connecting the rapid progress of commercial multiplexing, digitisation and data acquisition hardware together with a three-dimensional neural interface.
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http://dx.doi.org/10.1126/sciadv.aay2789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083623PMC
March 2020

High-Throughput Automated Olfactory Phenotyping of Group-Housed Mice.

Front Behav Neurosci 2019 17;13:267. Epub 2019 Dec 17.

Institute of Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.

Behavioral phenotyping of mice is often compromised by manual interventions of the experimenter and limited throughput. Here, we describe a fully automated behavior setup that allows for quantitative analysis of mouse olfaction with minimized experimenter involvement. Mice are group-housed and tagged with unique RFID chips. They can freely initiate trials and are automatically trained on a go/no-go task, learning to distinguish a rewarded from an unrewarded odor. Further, odor discrimination tasks and detailed training aspects can be set for each animal individually for automated execution without direct experimenter intervention. The procedure described here, from initial RFID implantation to discrimination of complex odor mixtures at high accuracy, can be completed within <2 months with cohorts of up to 25 male mice. Apart from the presentation of monomolecular odors, the setup can generate arbitrary mixtures and dilutions from any set of odors to create complex stimuli, enabling demanding behavioral analyses at high-throughput.
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http://dx.doi.org/10.3389/fnbeh.2019.00267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927946PMC
December 2019

Pioneers in CNS inhibition: 2. Charles Sherrington and John Eccles on inhibition in spinal and supraspinal structures.

Brain Res 2020 05 6;1734:146540. Epub 2019 Nov 6.

Department of Physiology, University of Arizona, PO Box 210093, Tucson, AZ 85721-0093, USA.

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 of neurons," and Eccles in 1963 for "discoveries concerning the ionic mechanisms involved in excitation and inhibition in central portions of the nerve cell membrane." Both spoke about central inhibition at their Nobel Prize Award Ceremonies. The subsequent publications of their talks were entitled "Inhibition as a coordinative factor" and "The ionic mechanism of postsynaptic inhibition", respectively. Sherrington's work on central inhibition spanned 41 years (1893-1934), and for Eccles 49 years (1928-1977). Sherrington first studied central inhibition by observing hind limb muscle responses to electrical (peripheral nerve) and mechanical (muscle) stimulation. He used muscle length and force measurements until the early 1900s and electromyography in the late 1920s. Eccles used these techniques while working with Sherrington, but later employed extracellular microelectrode recording in the spinal cord followed in 1951 by intracellular recording from spinal motoneurons. This considerably advanced our understanding of central inhibition. Sherrington's health was poor during his retirement years but he nonetheless made a small number of largely humanities contributions up to 1951, one year before his death at the age of 94. In contrast, Eccles retained his health and vigor until 3 years before his death and published prolifically on many subjects during his 22 years of official retirement. His last neuroscience article appeared in 1994 when he was 91. Despite poor health he continued thinking about his life-long interest, the mind-brain problem, and was attempting to complete his autobiography in the last years of his life.
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http://dx.doi.org/10.1016/j.brainres.2019.146540DOI Listing
May 2020

Targeted In Vivo Electroporation Using Nanoengineered Microelectrodes.

Methods Mol Biol 2020 ;2050:113-120

Behavioural Neurophysiology, Max-Planck-Institute for Medical Research, Heidelberg, Germany.

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 aiming for larger electroporation volumes. In this chapter, we describe the production of nanoengineered electroporation microelectrodes (NEMs), a practicable way to prepare glass microelectrodes providing a more even distribution around the tip of a pipette by using nanotechnological methods.
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http://dx.doi.org/10.1007/978-1-4939-9740-4_12DOI Listing
October 2020

AutonoMouse: High throughput operant conditioning reveals progressive impairment with graded olfactory bulb lesions.

PLoS One 2019 6;14(3):e0211571. Epub 2019 Mar 6.

The Francis Crick Institute, Neurophysiology of Behaviour Laboratory, London, United Kingdom.

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 for self-initiated conditioning of up to 25 group-housed, radio-frequency identification (RFID) tagged mice over periods of several months and >106 trials. We validate this "AutonoMouse" system in a series of olfactory behavioural tasks and show that acquired data is comparable to previous semi-manual approaches. Furthermore, we use AutonoMouse to systematically probe the impact of graded olfactory bulb lesions on olfactory behaviour, demonstrating that while odour discrimination in general is robust to even most extensive disruptions, small olfactory bulb lesions already impair odour detection. Discrimination learning of similar mixtures as well as learning speed are in turn reliably impacted by medium lesion sizes. The modular nature and open-source design of AutonoMouse should allow for similar robust and systematic assessments across neuroscience research areas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211571PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402634PMC
November 2019

Rapid task-dependent tuning of the mouse olfactory bulb.

Elife 2019 02 6;8. Epub 2019 Feb 6.

Sensory and Behavioural Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.

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 olfactory responses more discriminable through selective amplification in a demand-specific way.
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http://dx.doi.org/10.7554/eLife.43558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365054PMC
February 2019

Silicon Valley new focus on brain computer interface: hype or hope for new applications?

F1000Res 2018 21;7:1327. Epub 2018 Aug 21.

Department of Neurosurgery, Stanford University Medical Center, Brighton, USA.

In the last year there has been increasing interest and investment into developing devices to interact with the central nervous system, in particular developing a robust brain-computer interface (BCI). In this article, we review the most recent research advances and the current host of engineering and neurological challenges that must be overcome for clinical application. In particular, space limitations, isolation of targeted structures, replacement of probes following failure, delivery of nanomaterials and processing and understanding recorded data. Neural engineering has developed greatly over the past half-century, which has allowed for the development of better neural recording techniques and clinical translation of neural interfaces. Implementation of general purpose BCIs face a number of constraints arising from engineering, computational, ethical and neuroscientific factors that still have to be addressed. Electronics have become orders of magnitude smaller and computationally faster than neurons, however there is much work to be done in decoding the neural circuits. New interest and funding from the non-medical community may be a welcome catalyst for focused research and development; playing an important role in future advancements in the neuroscience community.
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http://dx.doi.org/10.12688/f1000research.15726.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343225PMC
November 2019

Sniffing Fast: Paradoxical Effects on Odor Concentration Discrimination at the Levels of Olfactory Bulb Output and Behavior.

eNeuro 2018 Sep-Oct;5(5). Epub 2018 Dec 26.

Neurophysiology of Behaviour Laboratory, Francis Crick Institute, London, NW1 1AT, UK.

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 mimics the effect of odor concentration increase at the level of both mitral and tufted cell (MTC) firing rate responses and temporal responses. Paradoxically, we find that mice are capable of discriminating fine concentration differences within short timescales despite highly variable sniffing behavior. One way that the olfactory system could differentiate between a change in sniffing and a change in concentration would be to receive information about the inhalation parameters in parallel with information about the odor. We find that the sniff-driven activity of MTCs without odor input is informative of the kind of inhalation that just occurred, allowing rapid detection of a change in inhalation. Thus, a possible reason for sniff modulation of the early olfactory system may be to directly inform downstream centers of nasal flow dynamics, so that an inference can be made about environmental concentration independent of sniff variance.
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http://dx.doi.org/10.1523/ENEURO.0148-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306510PMC
April 2019

Quantitative Association of Anatomical and Functional Classes of Olfactory Bulb Neurons.

J Neurosci 2018 08 5;38(33):7204-7220. Epub 2018 Jul 5.

Behavioural Neurophysiology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany,

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 population-wise morphological and physiological properties and a comprehensive classification based on quantitative parameters, however, is still lacking, impeding the analysis of microcircuits. Here, we provide multivariate clustering of 95 sampled cells from the GL of the mouse (male or female C57BL/6) OB and perform detailed morphological and physiological characterization for the seven computed JGC types. Using a classifier based on a subselection of parameters, we identified the neuron types in paired recordings to characterize their functional connectivity. We found that 4 of the 7 clusters comply with prevailing concepts of GL cell types, whereas the other 3 represent own distinct entities. We have labeled these entities horizontal superficial tufted cell (hSTC), vertical superficial tufted cell, and microglomerular cell (MGC): The hSTC is a tufted cell with a lateral dendrite that much like mitral cells and tufted cells receives excitatory inputs from the external tufted cell but likewise serves as an excitatory element for glomerular interneurons. The vertical superficial tufted cell, on the other hand, represents a tufted cell type with vertically projecting basal dendrites. We further define the MGC, characterized by a small dendritic tree and plateau action potentials. In addition to olfactory nerve-driven and external tufted cell driven interneurons, these MGCs represent a third functionally distinct type, the hSTC-driven interneurons. The presented correlative analysis helps to bridge the gap between branching patterns and cellular functional properties, permitting the integration of results from recordings, advanced morphological tools, and connectomics. The variance of neuron properties is a feature across mammalian cerebral circuits, contributing to signal processing and adding computational robustness to the networks. It is particularly noticeable in the glomerular layer of the olfactory bulb, the first site of olfactory information processing. We provide the first unbiased population-wise multivariate analysis to correlate morphological and physiological parameters of juxtaglomerular cells. We identify seven cell types, including four previously described neuron types, and identify further three distinct classes. The presented correlative analysis of morphological and physiological parameters gives an opportunity to predict morphological classes from physiological measurements or the functional properties of neurons from morphology and opens the way to integrate results from recordings, advanced morphological tools, and connectomics.
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http://dx.doi.org/10.1523/JNEUROSCI.0303-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096045PMC
August 2018

Active Sampling State Dynamically Enhances Olfactory Bulb Odor Representation.

Neuron 2018 06 31;98(6):1214-1228.e5. Epub 2018 May 31.

Neurophysiology of Behaviour Laboratory, Francis Crick Institute, London NW1 5AT, UK; Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6BT, UK. Electronic address:

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 cells (MTCs). Across these learning episodes, diverse response changes occur already during the first sniff cycle. Motivated mice develop active sniffing strategies across learning that robustly correspond to the odor response changes, resulting in enhanced odor representation. Evoking fast sniffing in different behavioral states demonstrates that response changes during active sampling exceed those predicted from feedforward input alone. Finally, response changes are highly correlated in tufted cells, but not mitral cells, indicating there are cell-type-specific effects on odor representation during active sampling. Altogether, we show that active sampling is strongly associated with enhanced OB responsiveness on rapid timescales.
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http://dx.doi.org/10.1016/j.neuron.2018.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030445PMC
June 2018

Functionalisation of Detonation Nanodiamond for Monodispersed, Soluble DNA-Nanodiamond Conjugates Using Mixed Silane Bead-Assisted Sonication Disintegration.

Sci Rep 2018 01 15;8(1):728. Epub 2018 Jan 15.

The Francis Crick Institute, 1 Midland Rd, Kings Cross, London, NW1 1AT, UK.

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 dispersion and solubility using an ultrasonic, mixed-silanization chemistry protocol based on the in situ Bead-Assisted Sonication Disintegration (BASD) silanization method. We use two silanes to achieve these properties: (1) 3-(trihydroxysilyl)propyl methylphosphonate (THPMP); a negatively charged silane that imparts high zeta potential and solubility in solution; and (2) (3-aminopropyl)triethoxysilane (APTES); a commonly used functional silane that contributes an amino group for subsequent bioconjugation. We target these amino groups for covalent conjugation to thiolated, single-stranded DNA oligomers using the heterobifunctional crosslinker sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (Sulfo-SMCC). The resulting DNA-DND conjugates are the smallest reported to date, as determined by Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM). The functionalisation method we describe is versatile and can be used to produce a wide variety of soluble DND-biomolecule conjugates.
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http://dx.doi.org/10.1038/s41598-017-18601-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768878PMC
January 2018

Viruses leave their stamp on single cells.

Nat Biotechnol 2018 01 18;36(1):42-44. Epub 2017 Dec 18.

Neurophysiology of Behaviour Laboratory, Francis Crick Institute, London, UK, and the Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK.

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http://dx.doi.org/10.1038/nbt.4043DOI Listing
January 2018

Building Bridges through Science.

Neuron 2017 Nov;96(4):730-735

The Scripps Research Institute, La Jolla, CA 92037, USA.

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.
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http://dx.doi.org/10.1016/j.neuron.2017.09.028DOI Listing
November 2017

The maps they are a-changin': plasticity in odor representation in interneurons.

Nat Neurosci 2017 01;20(2):128-129

Neurophysiology of Behaviour Lab, The Francis Crick Institute, London, UK.

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http://dx.doi.org/10.1038/nn.4484DOI Listing
January 2017

Massive normalization of olfactory bulb output in mice with a 'monoclonal nose'.

Elife 2016 05 13;5. Epub 2016 May 13.

Center for Interdisciplinary Research in Biology, Collège de France, INSERM U1050, CNRS UMR 7241, Paris, France.

Perturbations in neural circuits can provide mechanistic understanding of the neural correlates of behavior. In M71 transgenic mice with a "monoclonal nose", glomerular input patterns in the olfactory bulb are massively perturbed and olfactory behaviors are altered. To gain insights into how olfactory circuits can process such degraded inputs we characterized odor-evoked responses of olfactory bulb mitral cells and interneurons. Surprisingly, calcium imaging experiments reveal that mitral cell responses in M71 transgenic mice are largely normal, highlighting a remarkable capacity of olfactory circuits to normalize sensory input. In vivo whole cell recordings suggest that feedforward inhibition from olfactory bulb periglomerular cells can mediate this signal normalization. Together, our results identify inhibitory circuits in the olfactory bulb as a mechanistic basis for many of the behavioral phenotypes of mice with a "monoclonal nose" and highlight how substantially degraded odor input can be transformed to yield meaningful olfactory bulb output.
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http://dx.doi.org/10.7554/eLife.16335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919110PMC
May 2016

Divergent innervation of the olfactory bulb by distinct raphe nuclei.

J Comp Neurol 2015 Apr 14;523(5):805-13. Epub 2015 Jan 14.

Behavioural Neurophysiology, Max Planck Institute for Medical Research, Heidelberg, 69120, Germany; Champalimaud Centre for Neuroscience, Lisbon, 1400-038, Portugal.

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 fibers, particularly in the glomerular layer (GL), where they are thought to gate incoming signals from the olfactory nerve. The dorsal raphe nucleus (DRN) and the median raphe nucleus (MRN) are known to densely innervate the OB. The majority of such projections are thought to terminate in the GL, but this has not been explicitly tested. We sought to investigate this using recombinant adeno-associated viruses (rAAV)-mediated expression of green fluorescent protein (GFP)-synaptophysin targeted specifically to neurons of the DRN or the MRN. With DRN injections, labeled fibers were found mostly in the granule cell layer (GCL), not the GL. Conversely, dense labeling in the GL was observed with MRN injections, suggesting that the source of GL innervation is the MRN, not the DRN, as previously thought. The two raphe nuclei thus give dual innervation within the OB, with distinct innervation patterns.
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http://dx.doi.org/10.1002/cne.23713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328392PMC
April 2015

Penetration of cell membranes and synthetic lipid bilayers by nanoprobes.

Biophys J 2014 Nov;107(9):2091-100

Department of Materials Science and Engineering, Stanford University, Stanford, California. Electronic address:

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 characterization methods that are capable of following the process of membrane penetration with nanometer resolution. Although extensive work has examined the rupture of supported synthetic lipid bilayers, little is known about the applicability of these model systems to living cell membranes with complex lipid compositions, cytoskeletal attachment, and membrane proteins. Here, we describe atomic force microscopy (AFM) membrane penetration experiments in two parallel systems: live HEK293 cells and stacks of synthetic lipid bilayers. By using the same probes in both systems, we were able to clearly identify membrane penetration in synthetic bilayers and compare these events with putative membrane penetration events in cells. We examined membrane penetration forces for three tip geometries and 18 chemical modifications of the probe surface, and in all cases the median forces required to penetrate cellular and synthetic lipid bilayers with nanoprobes were greater than 1 nN. The penetration force was sensitive to the probe's sharpness, but not its surface chemistry, and the force did not depend on cell surface or cytoskeletal properties, with cells and lipid stacks yielding similar forces. This systematic assessment of penetration under various mechanical and chemical conditions provides insights into nanoprobe-cell interactions and informs the design of future intracellular nanoprobes.
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http://dx.doi.org/10.1016/j.bpj.2014.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223211PMC
November 2014

'Silent' mitral cells dominate odor responses in the olfactory bulb of awake mice.

Nat Neurosci 2014 Oct 27;17(10):1313-5. Epub 2014 Jul 27.

1] Behavioural Neurophysiology, Max Planck Institute for Medical Research, Heidelberg, Germany. [2] Division of Neurophysiology, MRC National Institute for Medical Research, London, UK. [3] Department of Anatomy and Cell Biology, Faculty of Medicine, University of Heidelberg, Heidelberg, Germany. [4] Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

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 in 'active' neurons. Thus, a previously missed M/TC subpopulation can exert powerful influence over the olfactory bulb.
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http://dx.doi.org/10.1038/nn.3768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176944PMC
October 2014

Independent control of gamma and theta activity by distinct interneuron networks in the olfactory bulb.

Nat Neurosci 2014 Sep 6;17(9):1208-16. Epub 2014 Jul 6.

1] Behavioural Neurophysiology, Max Planck Institute for Medical Research, Heidelberg, Germany. [2] Division of Neurophysiology, MRC National Institute for Medical Research, London, UK. [3] Department Anatomy and Cell Biology, Faculty of Medicine, University of Heidelberg, Heidelberg, Germany. [4] Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

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 implicated in rhythm generation are segregated into distinct layers, neatly separating local and global motifs. We combined intracellular recordings in vivo with circuit-specific optogenetic interference to examine the contribution of inhibition to rhythmic activity in the mouse olfactory bulb. We found that the two inhibitory circuits controlled rhythms on distinct timescales: local, glomerular networks coordinated theta activity, regulating baseline and odor-evoked inhibition, whereas granule cells orchestrated gamma synchrony and spike timing. Notably, granule cells did not contribute to baseline rhythms or sniff-coupled odor-evoked inhibition. Thus, activities on theta and gamma timescales are controlled by separate, dissociable inhibitory networks in the olfactory bulb.
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http://dx.doi.org/10.1038/nn.3760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146518PMC
September 2014

Sensory-evoked synaptic integration in cerebellar and cerebral cortical neurons.

Nat Rev Neurosci 2014 Feb 17;15(2):71-83. Epub 2014 Jan 17.

1] Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. [2] The Division of Neurophysiology, MRC National Institute for Medical Research, Mill Hill, London, NW7 1AA, UK.

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 inputs, most evoked synaptic activity generates only subthreshold membrane potential fluctuations. Sensory tuning of synaptic inputs is typically broad, but short-term dynamics and the interplay between excitation and inhibition restrict action potential firing to narrow windows of opportunity. We highlight the challenges and limitations of the use of somatic recordings in the study of synaptic integration and the importance of active dendritic mechanisms in sensory processing.
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http://dx.doi.org/10.1038/nrn3648DOI Listing
February 2014

Pioneers in CNS inhibition: 1. Ivan M. Sechenov, the first to clearly demonstrate inhibition arising in the brain.

Brain Res 2014 Feb 14;1548:20-48. Epub 2013 Dec 14.

School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW 2308, Australia.

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 prescient contributions to physiological psychology. In Russia, however, he is also revered as "the father of Russian physiology," because of his contributions to neurophysiology and other aspects of physiology including blood gases and respiration, the physiology and biomechanics of movement, and general physiology concepts that appeared in his textbooks and later works he helped translate from largely German sources. After graduation from Moscow University Medical School in 1856 he spent 3½ years in Germany and Austria where he attended lectures and conducted research under the direction of several prominent physiologists and biochemists. In his subsequent academic career he held positions at universities in St. Petersburg (1860-1870; 1876-1888), Odessa (1871-1876) and Moscow (1890-1905). From 1860 onwards he was acclaimed as a physiologist in academic circles. He was also well known in Russian society for his public lectures on physiology and his views on physiological psychology. The latter resulted in him being branded "politically unreliable" by the tsarist bureaucracy from 1863 onwards. Sechenov's first (1862) study on central inhibition remains his most memorable. He delayed the withdrawal of a frog's foot from a weak acid solution by chemical or electrical stimulation of selected parts of the central nervous system. He also noted similar effects on his own hand during co-activation of other sensory inputs by tickling or teeth gnashing.
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http://dx.doi.org/10.1016/j.brainres.2013.12.006DOI Listing
February 2014

Perceptual judgements and chronic imaging of altered odour maps indicate comprehensive stimulus template matching in olfaction.

Nat Commun 2013 ;4:2100

Department of Neuroscience, Physiology and Pharmacology, University College London, University Street, London, UK.

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 epithelial lesions. Lesions prevent mice from recognizing previously experienced odours and differentially delay discrimination learning of unrecognized and novel odour pairs. Poor recognition results not from mice experiencing an altered concentration of an odour but from perception of apparent novel qualities. Consistent with this, relative intensity of glomerular activity following lesions is altered compared with maps recorded in shams and by varying odour concentration. Together, these data show that odour recognition relies on comprehensively matching input patterns to a previously generated stimulus template. When encountering novel odours, access to all glomerular activity ensures rapid generation of new templates to perform accurate perceptual judgements.
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http://dx.doi.org/10.1038/ncomms3100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715885PMC
December 2013

Neuronal recordings with solid-conductor intracellular nanoelectrodes (SCINEs).

PLoS One 2012 15;7(8):e43194. Epub 2012 Aug 15.

Behavioural Neurophysiology, Max Planck Institute for Medical Research, Heidelberg, Germany.

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 membrane. Here we demonstrate that nanoengineered electrodes can be used to record neuronal transmembrane potentials in brain tissue without causing these physiological perturbations. Using focused ion beam milling, we have fabricated Solid-Conductor Intracellular NanoElectrodes (SCINEs), from conventional tungsten microelectrodes. SCINEs have tips that are <300 nm in diameter for several micrometers, but can be easily handled and can be inserted into brain tissue. Performing simultaneous whole-cell patch recordings, we show that SCINEs can record action potentials (APs) as well as slower, subthreshold neuronal potentials without altering cellular properties. These results show a key role for nanotechnology in the development of new electrical recording techniques in neuroscience.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0043194PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419643PMC
February 2013

Two distinct channels of olfactory bulb output.

Neuron 2012 Jul;75(2):320-9

Behavioural Neurophysiology, Max-Planck-Institute for Medical Research, Jahnstr. 29, 69120 Heidelberg, Germany.

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 to this rhythm, but to opposing phases of the sniff cycle. This phase shift is established by local inhibition that selectively delays mitral cell activity. Furthermore, while tufted cell phase is unperturbed in response to purely excitatory odorants, mitral cell phase is advanced in a graded, stimulus-dependent manner. Thus, phase separation by inhibition forms the basis for two distinct channels of olfactory processing.
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http://dx.doi.org/10.1016/j.neuron.2012.05.017DOI Listing
July 2012

Psychophysical properties of odor processing can be quantitatively described by relative action potential latency patterns in mitral and tufted cells.

Front Syst Neurosci 2012 9;6:30. Epub 2012 May 9.

Department of Neuroscience, Physiology and Pharmacology University College London, UK.

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 mitral and tufted cell (M/TC) population within an individual sampling cycle could account for the psychophysical properties of odor processing. To determine this we created an OB model (50,000 M/TCs) exhibiting hallmarks of published in vivo properties and used a template-matching algorithm to assess stimulus separation. Such an AP latency-based scheme showed high reproducibility and sensitivity such that odor stimuli could be reliably separated independent of concentration. As in behavioral experiments we found that very dissimilar odors ("A vs. B") were accurately and rapidly discerned while very similar odors (binary mixtures, 0.4A/0.6B vs. 0.6A/0.4B) required up to 90 ms longer. As in lesion studies we find that AP latency-based representation is rather insensitive to disruption of large regions of the OB. The AP latency-based scheme described here, therefore, captures both temporal and psychophysical properties of olfactory processing and suggests that the onset patterns of M/TC activity in the OB represent stimulus specific features of olfactory stimuli.
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http://dx.doi.org/10.3389/fnsys.2012.00030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348723PMC
October 2012

The surveillance state of behavioral automation.

Curr Opin Neurobiol 2012 Feb 24;22(1):170-6. Epub 2011 Nov 24.

Behavioural Neurophysiology, Max-Planck-Institute for Medical Research, Jahnstr. 29, 69120 Heidelberg, Germany.

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 disciplines (psychology, ethology and physiology) while producing insight into problems that were otherwise opaque. Ironically, a central theme of current automatization is to improve observation of animals in increasingly naturalistic environments. This is not just a return to 19th century priorities: the new observational methods provide unprecedented quantitation of actions and ever-closer integration with experimentation.
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http://dx.doi.org/10.1016/j.conb.2011.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398388PMC
February 2012