Publications by authors named "Fritjof Helmchen"

110 Publications

Neural Systems Under Change of Scale.

Front Comput Neurosci 2021 21;15:643148. Epub 2021 Apr 21.

Department of Neuroimaging, King's College London, London, United Kingdom.

We derive a theoretical construct that allows for the characterisation of both scalable and scale free systems within the dynamic causal modelling (DCM) framework. We define a dynamical system to be "scalable" if the same equation of motion continues to apply as the system changes in size. As an example of such a system, we simulate planetary orbits varying in size and show that our proposed methodology can be used to recover Kepler's third law from the timeseries. In contrast, a "scale free" system is one in which there is no characteristic length scale, meaning that images of such a system are statistically unchanged at different levels of magnification. As an example of such a system, we use calcium imaging collected in murine cortex and show that the dynamical critical exponent, as defined in renormalization group theory, can be estimated in an empirical biological setting. We find that a task-relevant region of the cortex is associated with higher dynamical critical exponents in task vs. spontaneous states and vice versa for a task-irrelevant region.
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http://dx.doi.org/10.3389/fncom.2021.643148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099030PMC
April 2021

Long-term self-renewing stem cells in the adult mouse hippocampus identified by intravital imaging.

Nat Neurosci 2021 02 21;24(2):225-233. Epub 2020 Dec 21.

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich, Switzerland.

Neural stem cells (NSCs) generate neurons throughout life in the mammalian hippocampus. However, the potential for long-term self-renewal of individual NSCs within the adult brain remains unclear. We used two-photon microscopy and followed NSCs that were genetically labeled through conditional recombination driven by the regulatory elements of the stem cell-expressed genes GLI family zinc finger 1 (Gli1) or achaete-scute homolog 1 (Ascl1). Through intravital imaging of NSCs and their progeny, we identify a population of Gli1-targeted NSCs showing long-term self-renewal in the adult hippocampus. In contrast, once activated, Ascl1-targeted NSCs undergo limited proliferative activity before they become exhausted. Using single-cell RNA sequencing, we show that Gli1- and Ascl1-targeted cells have highly similar yet distinct transcriptional profiles, supporting the existence of heterogeneous NSC populations with diverse behavioral properties. Thus, we here identify long-term self-renewing NSCs that contribute to the generation of new neurons in the adult hippocampus.
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http://dx.doi.org/10.1038/s41593-020-00759-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116750PMC
February 2021

Basomedial amygdala activity in mice reflects specific and general aversion uncontrollability.

Eur J Neurosci 2020 Dec 18. Epub 2020 Dec 18.

Preclinical Laboratory for Translational Research into Affective Disorders (PLaTRAD), Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zurich, Zurich, Switzerland.

Learning adaptive behaviour to control aversion is a major brain function. Detecting the absence of control is also important, although chronic uncontrollable aversion can impact maladaptively on stimulus processing in general. The mouse basomedial amygdala (BMA) contributes to aversion processing with high BMA activity associated with active behavioural responding. The overall aim of the present study was to investigate the associations between aversion (un)controllability, BMA activity and behaviour. Fibre photometry of GCaMP6-expressing BMA neuron populations was applied in freely behaving adult male mice during exposure to mild electrical shocks, and effects of specific or general (un)controllability were investigated. In a discrete learned helplessness (LH) effect paradigm, mice underwent discrete sessions of pre-exposure to either escapable shock (ES) or inescapable shock (IES) followed by an escape test. IES mice acquired fewer escape attempts than ES mice, and this co-occurred with higher aversion-related BMA activity in the IES group. After 30 days, ES and IES mice were allocated equally to either chronic social stress (CSS)-exposure to continuous uncontrollable social aversion-or control handling (CON), and on days 5 and 15 underwent an IES session. CSS mice made fewer escape attempts than CON mice, and this was now associated with lower aversion-related BMA activity in the CSS group. These findings suggest that mouse BMA activity is higher when discrete aversion is uncontrollable but becomes lower following chronic uncontrollable aversion exposure. Therefore, BMA activity could be a neural marker of adaptive and maladaptive states consequent to specific and general uncontrollability, respectively.
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http://dx.doi.org/10.1111/ejn.15090DOI Listing
December 2020

Developmental divergence of sensory stimulus representation in cortical interneurons.

Nat Commun 2020 11 12;11(1):5729. Epub 2020 Nov 12.

Laboratory of Neural Circuit Assembly, Brain Research Institute, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.

Vasocative-intestinal-peptide (VIP) and somatostatin (SST) interneurons are involved in modulating barrel cortex activity and perception during active whisking. Here we identify a developmental transition point of structural and functional rearrangements onto these interneurons around the start of active sensation at P14. Using in vivo two-photon Ca imaging, we find that before P14, both interneuron types respond stronger to a multi-whisker stimulus, whereas after P14 their responses diverge, with VIP cells losing their multi-whisker preference and SST neurons enhancing theirs. Additionally, we find that Ca signaling dynamics increase in precision as the cells and network mature. Rabies virus tracings followed by tissue clearing, as well as photostimulation-coupled electrophysiology reveal that SST cells receive higher cross-barrel inputs compared to VIP neurons at both time points. In addition, whereas prior to P14 both cell types receive direct input from the sensory thalamus, after P14 VIP cells show reduced inputs and SST cells largely shift to motor-related thalamic nuclei.
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http://dx.doi.org/10.1038/s41467-020-19427-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661508PMC
November 2020

Sensory and Behavioral Components of Neocortical Signal Flow in Discrimination Tasks with Short-Term Memory.

Neuron 2021 01 6;109(1):135-148.e6. Epub 2020 Nov 6.

Brain Research Institute, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich, Zurich, Switzerland. Electronic address:

In the neocortex, each sensory modality engages distinct sensory areas that route information to association areas. Where signal flow converges for maintaining information in short-term memory and how behavior may influence signal routing remain open questions. Using wide-field calcium imaging, we compared cortex-wide neuronal activity in layer 2/3 for mice trained in auditory and tactile tasks with delayed response. In both tasks, mice were either active or passive during stimulus presentation, moving their body or sitting quietly. Irrespective of behavioral strategy, auditory and tactile stimulation activated distinct subdivisions of the posterior parietal cortex, anterior area A and rostrolateral area RL, which held stimulus-related information necessary for the respective tasks. In the delay period, in contrast, behavioral strategy rather than sensory modality determined short-term memory location, with activity converging frontomedially in active trials and posterolaterally in passive trials. Our results suggest behavior-dependent routing of sensory-driven cortical signals flow from modality-specific posterior parietal cortex (PPC) subdivisions to higher association areas.
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http://dx.doi.org/10.1016/j.neuron.2020.10.017DOI Listing
January 2021

Value-guided remapping of sensory cortex by lateral orbitofrontal cortex.

Nature 2020 09 3;585(7824):245-250. Epub 2020 Sep 3.

Laboratory of Neural Circuit Dynamics, Brain Research Institute, University of Zurich, Zurich, Switzerland.

Adaptive behaviour crucially depends on flexible decision-making, which in mammals relies on the frontal cortex, specifically the orbitofrontal cortex (OFC). How OFC encodes decision variables and instructs sensory areas to guide adaptive behaviour are key open questions. Here we developed a reversal learning task for head-fixed mice, monitored the activity of neurons of the lateral OFC using two-photon calcium imaging and investigated how OFC dynamically interacts with primary somatosensory cortex (S1). Mice learned to discriminate 'go' from 'no-go' tactile stimuli and adapt their behaviour upon reversal of stimulus-reward contingency ('rule switch'). Imaging individual neurons longitudinally across all behavioural phases revealed a distinct engagement of S1 and lateral OFC, with S1 neural activity reflecting initial task learning, whereas lateral OFC neurons responded saliently and transiently to the rule switch. We identified direct long-range projections from lateral OFC to S1 that can feed this activity back to S1 as value prediction error. This top-down signal updated sensory representations in S1 by functionally remapping responses in a subpopulation of neurons that was sensitive to reward history. Functional remapping crucially depended on top-down feedback as chemogenetic silencing of lateral OFC neurons disrupted reversal learning, as well as plasticity in S1. The dynamic interaction of lateral OFC with sensory cortex thus implements computations critical for value prediction that are history dependent and error based, providing plasticity essential for flexible decision-making.
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http://dx.doi.org/10.1038/s41586-020-2704-zDOI Listing
September 2020

Opto-E-Dura: A Soft, Stretchable ECoG Array for Multimodal, Multiscale Neuroscience.

Adv Healthc Mater 2020 09 21;9(17):e2000814. Epub 2020 Jul 21.

Laboratory of Neural Circuit Dynamics, Brain Research Institute, University of Zurich, Zurich, 8057, Switzerland.

Soft, stretchable materials hold great promise for the fabrication of biomedical devices due to their capacity to integrate gracefully with and conform to biological tissues. Conformal devices are of particular interest in the development of brain interfaces where rigid structures can lead to tissue damage and loss of signal quality over the lifetime of the implant. Interfaces to study brain function and dysfunction increasingly require multimodal access in order to facilitate measurement of diverse physiological signals that span the disparate temporal and spatial scales of brain dynamics. Here the Opto-e-Dura, a soft, stretchable, 16-channel electrocorticography array that is optically transparent is presented. Its compatibility with diverse optical and electrical readouts is demonstrated enabling multimodal studies that bridge spatial and temporal scales. The device is chronically stable for weeks, compatible with wide-field and 2-photon calcium imaging and permits the repeated insertion of penetrating multielectrode arrays. As the variety of sensors and effectors realizable on soft, stretchable substrates expands, similar devices that provide large-scale, multimodal access to the brain will continue to improve fundamental understanding of brain function.
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http://dx.doi.org/10.1002/adhm.202000814DOI Listing
September 2020

Conservation laws by virtue of scale symmetries in neural systems.

PLoS Comput Biol 2020 05 4;16(5):e1007865. Epub 2020 May 4.

Department of Neuroimaging, King's College London, London, United Kingdom.

In contrast to the symmetries of translation in space, rotation in space, and translation in time, the known laws of physics are not universally invariant under transformation of scale. However, a special case exists in which the action is scale invariant if it satisfies the following two constraints: 1) it must depend upon a scale-free Lagrangian, and 2) the Lagrangian must change under scale in the same way as the inverse time, [Formula: see text]. Our contribution lies in the derivation of a generalised Lagrangian, in the form of a power series expansion, that satisfies these constraints. This generalised Lagrangian furnishes a normal form for dynamic causal models-state space models based upon differential equations-that can be used to distinguish scale symmetry from scale freeness in empirical data. We establish face validity with an analysis of simulated data, in which we show how scale symmetry can be identified and how the associated conserved quantities can be estimated in neuronal time series.
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http://dx.doi.org/10.1371/journal.pcbi.1007865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224579PMC
May 2020

Cortical Excitation:Inhibition Imbalance Causes Abnormal Brain Network Dynamics as Observed in Neurodevelopmental Disorders.

Cereb Cortex 2020 07;30(9):4922-4937

Neural Control of Movement Lab, HEST, ETH Zürich, 8093 Zurich, Switzerland.

Abnormal brain development manifests itself at different spatial scales. However, whether abnormalities at the cellular level can be diagnosed from network activity measured with functional magnetic resonance imaging (fMRI) is largely unknown, yet of high clinical relevance. Here a putative mechanism reported in neurodevelopmental disorders, that is, excitation-to-inhibition ratio (E:I), was chemogenetically increased within cortical microcircuits of the mouse brain and measured via fMRI. Increased E:I caused a significant "reduction" of long-range connectivity, irrespective of whether excitatory neurons were facilitated or inhibitory Parvalbumin (PV) interneurons were suppressed. Training a classifier on fMRI signals, we were able to accurately classify cortical areas exhibiting increased E:I. This classifier was validated in an independent cohort of Fmr1y/- knockout mice, a model for autism with well-documented loss of parvalbumin neurons and chronic alterations of E:I. Our findings demonstrate a promising novel approach towards inferring microcircuit abnormalities from macroscopic fMRI measurements.
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http://dx.doi.org/10.1093/cercor/bhaa084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391279PMC
July 2020

Spatiotemporal refinement of signal flow through association cortex during learning.

Nat Commun 2020 04 8;11(1):1744. Epub 2020 Apr 8.

Brain Research Institute, University of Zurich, CH-8057, Zurich, Switzerland.

Association areas in neocortex encode novel stimulus-outcome relationships, but the principles of their engagement during task learning remain elusive. Using chronic wide-field calcium imaging, we reveal two phases of spatiotemporal refinement of layer 2/3 cortical activity in mice learning whisker-based texture discrimination in the dark. Even before mice reach learning threshold, association cortex-including rostro-lateral (RL), posteromedial (PM), and retrosplenial dorsal (RD) areas-is generally suppressed early during trials (between auditory start cue and whisker-texture touch). As learning proceeds, a spatiotemporal activation sequence builds up, spreading from auditory areas to RL immediately before texture touch (whereas PM and RD remain suppressed) and continuing into barrel cortex, which eventually efficiently discriminates between textures. Additional correlation analysis substantiates this diverging learning-related refinement within association cortex. Our results indicate that a pre-learning phase of general suppression in association cortex precedes a learning-related phase of task-specific signal flow enhancement.
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http://dx.doi.org/10.1038/s41467-020-15534-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142160PMC
April 2020

Context-dependent limb movement encoding in neuronal populations of motor cortex.

Nat Commun 2019 10 23;10(1):4812. Epub 2019 Oct 23.

Laboratory of Neural Circuit Dynamics, Brain Research Institute, University of Zurich, Zurich, Switzerland.

Neuronal networks of the mammalian motor cortex (M1) are important for dexterous control of limb joints. Yet it remains unclear how encoding of joint movement in M1 depends on varying environmental contexts. Using calcium imaging we measured neuronal activity in layer 2/3 of the M1 forelimb region while mice grasped regularly or irregularly spaced ladder rungs during locomotion. We found that population coding of forelimb joint movements is sparse and varies according to the flexibility demanded from individual joints in the regular and irregular context, even for equivalent grasping actions across conditions. This context-dependence of M1 encoding emerged during task learning, fostering higher precision of grasping actions, but broke apart upon silencing of projections from secondary motor cortex (M2). These findings suggest that M1 exploits information from M2 to adapt encoding of joint movements to the flexibility demands of distinct familiar contexts, thereby increasing the accuracy of motor output.
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http://dx.doi.org/10.1038/s41467-019-12670-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811620PMC
October 2019

The mesoSPIM initiative: open-source light-sheet microscopes for imaging cleared tissue.

Nat Methods 2019 11 16;16(11):1105-1108. Epub 2019 Sep 16.

Brain Research Institute, University of Zurich, Zurich, Switzerland.

Light-sheet microscopy is an ideal technique for imaging large cleared samples; however, the community is still lacking instruments capable of producing volumetric images of centimeter-sized cleared samples with near-isotropic resolution within minutes. Here, we introduce the mesoscale selective plane-illumination microscopy initiative, an open-hardware project for building and operating a light-sheet microscope that addresses these challenges and is compatible with any type of cleared or expanded sample ( www.mesospim.org ).
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http://dx.doi.org/10.1038/s41592-019-0554-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824906PMC
November 2019

Functional Architecture and Encoding of Tactile Sensorimotor Behavior in Rat Posterior Parietal Cortex.

J Neurosci 2019 09 22;39(37):7332-7343. Epub 2019 Jul 22.

Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam 1081 HV, The Netherlands,

The posterior parietal cortex (PPC) in rodents is reciprocally connected to primary somatosensory and vibrissal motor cortices. The PPC neuronal circuitry could thus encode and potentially integrate incoming somatosensory information and whisker motor output. However, the information encoded across PPC layers during refined sensorimotor behavior remains largely unknown. To uncover the sensorimotor features represented in PPC during voluntary whisking and object touch, we performed loose-patch single-unit recordings and extracellular recordings of ensemble activity, covering all layers of PPC in anesthetized and awake, behaving male rats. First, using single-cell receptive field mapping, we revealed the presence of coarse somatotopy along the mediolateral axis in PPC. Second, we found that spiking activity was modulated during exploratory whisking in layers 2-4 and layer 6, but not in layer 5 of awake, behaving rats. Population spiking activity preceded actual movement, and whisker trajectory endpoints could be decoded by population spiking, suggesting that PPC is involved in movement planning. Finally, population spiking activity further increased in response to active whisker touch but only in PPC layers 2-4. Thus, we find layer-specific processing, which emphasizes the computational role of PPC during whisker sensorimotor behavior. The posterior parietal cortex (PPC) is thought to merge information on motor output and sensory input to orchestrate interaction with the environment, but the function of different PPC microcircuit components is poorly understood. We recorded neuronal activity in rat PPC during sensorimotor behavior involving motor and sensory pathways. We uncovered that PPC layers have dedicated function: motor and sensory information is merged in layers 2-4; layer 6 predominantly represents motor information. Collectively, PPC activity predicts future motor output, thus entailing a motor plan. Our results are important for understanding how PPC computationally processes motor output and sensory input. This understanding may facilitate decoding of brain activity when using brain-machine interfaces to overcome loss of function after, for instance, spinal cord injury.
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http://dx.doi.org/10.1523/JNEUROSCI.0693-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759035PMC
September 2019

Layer-specific integration of locomotion and sensory information in mouse barrel cortex.

Nat Commun 2019 06 13;10(1):2585. Epub 2019 Jun 13.

Brain Research Institute, University of Zurich, Zurich, Switzerland.

During navigation, rodents continually sample the environment with their whiskers. How locomotion modulates neuronal activity in somatosensory cortex, and how it is integrated with whisker-touch remains unclear. Here, we compared neuronal activity in layer 2/3 (L2/3) and L5 of barrel cortex using calcium imaging in mice running in a tactile virtual reality. Both layers increase their activity during running and concomitant whisking, in the absence of touch. Fewer neurons are modulated by whisking alone. Whereas L5 neurons respond transiently to wall-touch during running, L2/3 neurons show sustained activity. Consistently, neurons encoding running-with-touch are more abundant in L2/3 and they encode the run-speed better during touch. Few neurons across layers were also sensitive to abrupt perturbations of tactile flow during running. In summary, locomotion significantly enhances barrel cortex activity across layers with L5 neurons mainly reporting changes in touch conditions and L2/3 neurons continually integrating tactile stimuli with running.
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http://dx.doi.org/10.1038/s41467-019-10564-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565743PMC
June 2019

High-density multi-fiber photometry for studying large-scale brain circuit dynamics.

Nat Methods 2019 06 13;16(6):553-560. Epub 2019 May 13.

Brain Research Institute, University of Zurich, Zurich, Switzerland.

Animal behavior originates from neuronal activity distributed across brain-wide networks. However, techniques available to assess large-scale neural dynamics in behaving animals remain limited. Here we present compact, chronically implantable, high-density arrays of optical fibers that enable multi-fiber photometry and optogenetic perturbations across many regions in the mammalian brain. In mice engaged in a texture discrimination task, we achieved simultaneous photometric calcium recordings from networks of 12-48 brain regions, including striatal, thalamic, hippocampal and cortical areas. Furthermore, we optically perturbed subsets of regions in VGAT-ChR2 mice by targeting specific fiber channels with a spatial light modulator. Perturbation of ventral thalamic nuclei caused distributed network modulation and behavioral deficits. Finally, we demonstrate multi-fiber photometry in freely moving animals, including simultaneous recordings from two mice during social interaction. High-density multi-fiber arrays are versatile tools for the investigation of large-scale brain dynamics during behavior.
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http://dx.doi.org/10.1038/s41592-019-0400-4DOI Listing
June 2019

Temporal refinement of sensory-evoked activity across layers in developing mouse barrel cortex.

Eur J Neurosci 2019 09 2;50(6):2955-2969. Epub 2019 May 2.

Institute of Physiology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Rhythmic whisking behavior in rodents fully develops during a critical period about 2 weeks after birth, in parallel with the maturation of other sensory modalities and the onset of exploratory locomotion. How whisker-related sensory processing develops during this period in the primary somatosensory cortex (S1) remains poorly understood. Here, we characterized neuronal activity evoked by single- or dual-whisker stimulation patterns in developing S1, before, during and after the occurrence of active whisking. Employing multi-electrode recordings in all layers of barrel cortex in urethane-anesthetized mice, we find layer-specific changes in multi-unit activity for principal and neighboring barrel columns. While whisker stimulation evoked similar early responses (0-50 ms post-stimulus) across development, the late response (50-150 ms post-stimulus) decreased in all layers with age. Furthermore, peak onset times and the duration of the late response decreased in all layers across age groups. Responses to paired-pulse stimulation showed increases in spiking precision and in paired-pulse ratios in all cortical layers during development. Sequential activation of two neighboring whiskers with varying stimulus intervals evoked distinct response profiles in the activated barrel columns, depending on the direction and temporal separation of the stimuli. In conclusion, our findings indicate that the temporal sharpening of sensory-evoked activity coincides with the onset of active whisking.
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http://dx.doi.org/10.1111/ejn.14413DOI Listing
September 2019

Tissue Clearing and Light Sheet Microscopy: Imaging the Unsectioned Adult Zebra Finch Brain at Cellular Resolution.

Front Neuroanat 2019 14;13:13. Epub 2019 Feb 14.

Department of Behavioral Neurobiology, Max Planck Institute for Ornithology, Seewiesen, Germany.

The inherent complexity of brain tissue, with brain cells intertwining locally and projecting to distant regions, has made three-dimensional visualization of intact brains a highly desirable but challenging task in neuroscience. The natural opaqueness of tissue has traditionally limited researchers to techniques short of single cell resolution such as computer tomography or magnetic resonance imaging. By contrast, techniques with single-cell resolution required mechanical slicing into thin sections, which entails tissue distortions that severely hinder accurate reconstruction of large volumes. Recent developments in tissue clearing and light sheet microscopy have made it possible to investigate large volumes at micrometer resolution. The value of tissue clearing has been shown in a variety of tissue types and animal models. However, its potential for examining the songbird brain remains unexplored. Songbirds are an established model system for the study of vocal learning and sensorimotor control. They share with humans the capacity to adapt vocalizations based on auditory input. Song learning and production are controlled in songbirds by the song system, which forms a network of interconnected discrete brain nuclei. Here, we use the CUBIC and iDISCO+ protocols for clearing adult songbird brain tissue. Combined with light sheet imaging, we show the potential of tissue clearing for the investigation of connectivity between song nuclei, as well as for neuroanatomy and brain vasculature studies.
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http://dx.doi.org/10.3389/fnana.2019.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382697PMC
February 2019

iDISCO+ for the Study of Neuroimmune Architecture of the Rat Auditory Brainstem.

Front Neuroanat 2019 13;13:15. Epub 2019 Feb 13.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

The lower stations of the auditory system display a complex anatomy. The inner ear labyrinth is composed of several interconnecting membranous structures encased in cavities of the temporal bone, and the cerebellopontine angle contains fragile structures such as meningeal folds, the choroid plexus (CP), and highly variable vascular formations. For this reason, most histological studies of the auditory system have either focused on the inner ear or the CNS by physically detaching the temporal bone from the brainstem. However, several studies of neuroimmune interactions have pinpointed the importance of structures such as meninges and CP; in the auditory system, an immune function has also been suggested for inner ear structures such as the endolymphatic duct (ED) and sac. All these structures are thin, fragile, and have complex 3D shapes. In order to study the immune cell populations located on these structures and their relevance to the inner ear and auditory brainstem in health and disease, we obtained a clarified-decalcified preparation of the rat hindbrain still attached to the intact temporal bone. This preparation may be immunolabeled using a clearing protocol (based on iDISCO+) to show location and functional state of immune cells. The observed macrophage distribution suggests the presence of CP-mediated communication pathways between the inner ear and the cochlear nuclei.
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http://dx.doi.org/10.3389/fnana.2019.00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381022PMC
February 2019

Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response.

Brain 2019 04;142(4):885-902

Department of Neurosurgery, Clinical Neuroscience Center, Zurich University Hospital, Zurich University, Zurich, Switzerland.

Brain calcifications are commonly detected in aged individuals and accompany numerous brain diseases, but their functional importance is not understood. In cases of primary familial brain calcification, an autosomally inherited neuropsychiatric disorder, the presence of bilateral brain calcifications in the absence of secondary causes of brain calcification is a diagnostic criterion. To date, mutations in five genes including solute carrier 20 member 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), myogenesis regulating glycosidase (MYORG), platelet-derived growth factor B (PDGFB) and platelet-derived growth factor receptor β (PDGFRB), are considered causal. Previously, we have reported that mutations in PDGFB in humans are associated with primary familial brain calcification, and mice hypomorphic for PDGFB (Pdgfbret/ret) present with brain vessel calcifications in the deep regions of the brain that increase with age, mimicking the pathology observed in human mutation carriers. In this study, we characterize the cellular environment surrounding calcifications in Pdgfbret/ret animals and show that cells around vessel-associated calcifications express markers for osteoblasts, osteoclasts and osteocytes, and that bone matrix proteins are present in vessel-associated calcifications. Additionally, we also demonstrate the osteogenic environment around brain calcifications in genetically confirmed primary familial brain calcification cases. We show that calcifications cause oxidative stress in astrocytes and evoke expression of neurotoxic astrocyte markers. Similar to previously reported human primary familial brain calcification cases, we describe high interindividual variation in calcification load in Pdgfbret/ret animals, as assessed by ex vivo and in vivo quantification of calcifications. We also report that serum of Pdgfbret/ret animals does not differ in calcification propensity from control animals and that vessel calcification occurs only in the brains of Pdgfbret/ret animals. Notably, ossification of vessels and astrocytic neurotoxic response is associated with specific behavioural and cognitive alterations, some of which are associated with primary familial brain calcification in a subset of patients.
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http://dx.doi.org/10.1093/brain/awz032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439320PMC
April 2019

A brain-wide functional map of the serotonergic responses to acute stress and fluoxetine.

Nat Commun 2019 01 21;10(1):350. Epub 2019 Jan 21.

Neuroscience Center Zurich, Winterthurerstr. 190, CH-8057, Zurich, Switzerland.

Central serotonin (5-HT) orchestrates myriad cognitive processes and lies at the core of many stress-related psychiatric illnesses. However, the basic relationship between its brain-wide axonal projections and functional dynamics is not known. Here we combine optogenetics and fMRI to produce a brain-wide 5-HT evoked functional map. We find that DRN photostimulation leads to an increase in the hemodynamic response in the DRN itself, while projection areas predominately exhibit a reduction of cerebral blood volume mirrored by suppression of cortical delta oscillations. We find that the regional distribution of post-synaptically expressed 5-HT receptors better correlates with DRN 5-HT functional connectivity than anatomical projections. Our work suggests that neuroarchitecture is not the primary determinant of function for the DRN 5-HT. With respect to two 5-HT elevating stimuli, we find that acute stress leads to circuit-wide blunting of the DRN output, while the SSRI fluoxetine noticeably enhances DRN functional connectivity. These data provide fundamental insight into the brain-wide functional dynamics of the 5-HT projection system.
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http://dx.doi.org/10.1038/s41467-018-08256-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341094PMC
January 2019

Prion pathogenesis is unaltered in a mouse strain with a permeable blood-brain barrier.

PLoS Pathog 2018 11 29;14(11):e1007424. Epub 2018 Nov 29.

Institute of Neuropathology, University Hospital Zürich, Zürich University, Zürich, Switzerland.

Transmissible spongiform encephalopathies (TSEs) are caused by the prion, which consists essentially of PrPSc, an aggregated, conformationally modified form of the cellular prion protein (PrPC). Although TSEs can be experimentally transmitted by intracerebral inoculation, most instances of infection in the field occur through extracerebral routes. The epidemics of kuru and variant Creutzfeldt-Jakob disease were caused by dietary exposure to prions, and parenteral administration of prion-contaminated hormones has caused hundreds of iatrogenic TSEs. In all these instances, the development of postexposure prophylaxis relies on understanding of how prions propagate from the site of entry to the brain. While much evidence points to lymphoreticular invasion followed by retrograde transfer through peripheral nerves, prions are present in the blood and may conceivably cross the blood-brain barrier directly. Here we have addressed the role of the blood-brain barrier (BBB) in prion disease propagation using Pdgfbret/ret mice which possess a highly permeable BBB. We found that Pdgfbret/ret mice have a similar prion disease incubation time as their littermate controls regardless of the route of prion transmission. These surprising results indicate that BBB permeability is irrelevant to the initiation of prion disease, even when prions are administered parenterally.
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http://dx.doi.org/10.1371/journal.ppat.1007424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264140PMC
November 2018

Behavioral Strategy Determines Frontal or Posterior Location of Short-Term Memory in Neocortex.

Neuron 2018 08 9;99(4):814-828.e7. Epub 2018 Aug 9.

Brain Research Institute, University of Zurich, Zurich 8057, Switzerland; Neuroscience Center Zurich, Zurich 8057, Switzerland. Electronic address:

The location of short-term memory in mammalian neocortex remains elusive. Here we show that distinct neocortical areas maintain short-term memory depending on behavioral strategy. Using wide-field and single-cell calcium imaging, we measured layer 2/3 neuronal activity in mice performing a whisker-based texture discrimination task with delayed response. Mice either deployed an active strategy-engaging their body toward the approaching texture-or passively awaited the touch. Independent of strategy, whisker-related posterior areas encoded choice early after touch. During the delay, in contrast, persistent cortical activity was located medio-frontally in active trials but in a lateral posterior area in passive trials. Perturbing these areas impaired performance for the associated strategy and also provoked strategy switches. Frontally maintained information related to future action, whereas activity in the posterior cortex reflected past stimulus identity. Thus, depending on behavioral strategy, cortical activity is routed differentially to hold information either frontally or posteriorly before converging to similar action.
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http://dx.doi.org/10.1016/j.neuron.2018.07.029DOI Listing
August 2018

Sensory representation of an auditory cued tactile stimulus in the posterior parietal cortex of the mouse.

Sci Rep 2018 05 17;8(1):7739. Epub 2018 May 17.

Brain Research Institute, University of Zurich, Zurich, Switzerland.

Sensory association cortices receive diverse inputs with their role in representing and integrating multi-sensory content remaining unclear. Here we examined the neuronal correlates of an auditory-tactile stimulus sequence in the posterior parietal cortex (PPC) using 2-photon calcium imaging in awake mice. We find that neuronal subpopulations in layer 2/3 of PPC reliably represent texture-touch events, in addition to auditory cues that presage the incoming tactile stimulus. Notably, altering the flow of sensory events through omission of the cued texture touch elicited large responses in a subset of neurons hardly responsive to or even inhibited by the tactile stimuli. Hence, PPC neurons were able to discriminate not only tactile stimulus features (i.e., texture graininess) but also between the presence and omission of the texture stimulus. Whereas some of the neurons responsive to texture omission were driven by looming-like auditory sounds others became recruited only with tactile sensory experience. These findings indicate that layer 2/3 neuronal populations in PPC potentially encode correlates of expectancy in addition to auditory and tactile stimuli.
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http://dx.doi.org/10.1038/s41598-018-25891-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958066PMC
May 2018

Fiber-optic implant for simultaneous fluorescence-based calcium recordings and BOLD fMRI in mice.

Nat Protoc 2018 05 29;13(5):840-855. Epub 2018 Mar 29.

Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Zurich, Switzerland.

Despite the growing popularity of blood oxygen level-dependent (BOLD) functional MRI (fMRI), understanding of its underlying principles is still limited. This protocol describes a technique for simultaneous measurement of neural activity using fluorescent calcium indicators together with the corresponding hemodynamic BOLD fMRI response in the mouse brain. Our early work using small-molecule fluorophores in rats gave encouraging results but was limited to acute measurements using synthetic dyes. Our latest procedure combines fMRI with optical detection of cell-type-specific virally delivered GCaMP6, a genetically encoded calcium indicator (GECI). GCaMP6 fluorescence, which increases upon calcium binding, is collected by a chronically implanted optical fiber, allowing longitudinal studies in mice. The chronic implant, placed horizontally on the skull, has an angulated tip that reflects light into the brain and is connected via fiber optics to a remote optical setup. The technique allows access to the neocortex and does not require adaptations of commercial MRI hardware. The hybrid approach permits fiber-optic calcium recordings with simultaneous artifact-free BOLD fMRI with full brain coverage and 1-s temporal resolution using standard gradient-echo echo-planar imaging (GE-EPI) sequences. The method provides robust, cell-type-specific readouts to link neural activity to BOLD signals, as emonstrated for task-free ('resting-state') conditions and in response to hind-paw stimulation. These results highlight the power of fiber photometry combined with fMRI, which we aim to further advance in this protocol. The approach can be easily adapted to study other molecular processes using suitable fluorescent indicators.
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http://dx.doi.org/10.1038/nprot.2018.003DOI Listing
May 2018

Live imaging of neurogenesis in the adult mouse hippocampus.

Science 2018 02;359(6376):658-662

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland.

Neural stem and progenitor cells (NSPCs) generate neurons throughout life in the mammalian hippocampus. We used chronic in vivo imaging and followed genetically labeled individual NSPCs and their progeny in the mouse hippocampus for up to 2 months. We show that NSPCs targeted by the endogenous Achaete-scute homolog 1 (Ascl1) promoter undergo limited rounds of symmetric and asymmetric divisions, eliciting a burst of neurogenic activity, after which they are lost. Further, our data reveal unexpected asymmetric divisions of nonradial glia-like NSPCs. Cell fates of Ascl1-labeled lineages suggest a developmental-like program involving a sequential transition from a proliferative to a neurogenic phase. By providing a comprehensive description of lineage relationships, from dividing NSPCs to newborn neurons integrating into the hippocampal circuitry, our data offer insight into how NSPCs support life-long hippocampal neurogenesis.
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http://dx.doi.org/10.1126/science.aao5056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986926PMC
February 2018

A Sensitive Dynamic and Active Pixel Vision Sensor for Color or Neural Imaging Applications.

IEEE Trans Biomed Circuits Syst 2018 02;12(1):123-136

Applications requiring detection of small visual contrast require high sensitivity. Event cameras can provide higher dynamic range (DR) and reduce data rate and latency, but most existing event cameras have limited sensitivity. This paper presents the results of a 180-nm Towerjazz CIS process vision sensor called SDAVIS192. It outputs temporal contrast dynamic vision sensor (DVS) events and conventional active pixel sensor frames. The SDAVIS192 improves on previous DAVIS sensors with higher sensitivity for temporal contrast. The temporal contrast thresholds can be set down to 1% for negative changes in logarithmic intensity (OFF events) and down to 3.5% for positive changes (ON events). The achievement is possible through the adoption of an in-pixel preamplification stage. This preamplifier reduces the effective intrascene DR of the sensor (70 dB for OFF and 50 dB for ON), but an automated operating region control allows up to at least 110-dB DR for OFF events. A second contribution of this paper is the development of characterization methodology for measuring DVS event detection thresholds by incorporating a measure of signal-to-noise ratio (SNR). At average SNR of 30 dB, the DVS temporal contrast threshold fixed pattern noise is measured to be 0.3%-0.8% temporal contrast. Results comparing monochrome and RGBW color filter array DVS events are presented. The higher sensitivity of SDAVIS192 make this sensor potentially useful for calcium imaging, as shown in a recording from cultured neurons expressing calcium sensitive green fluorescent protein GCaMP6f.
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http://dx.doi.org/10.1109/TBCAS.2017.2759783DOI Listing
February 2018

Specific excitatory connectivity for feature integration in mouse primary visual cortex.

PLoS Comput Biol 2017 12 14;13(12):e1005888. Epub 2017 Dec 14.

Laboratory of Neural Circuit Dynamics, Brain Research Institute, University of Zurich, Zurich, Switzerland.

Local excitatory connections in mouse primary visual cortex (V1) are stronger and more prevalent between neurons that share similar functional response features. However, the details of how functional rules for local connectivity shape neuronal responses in V1 remain unknown. We hypothesised that complex responses to visual stimuli may arise as a consequence of rules for selective excitatory connectivity within the local network in the superficial layers of mouse V1. In mouse V1 many neurons respond to overlapping grating stimuli (plaid stimuli) with highly selective and facilitatory responses, which are not simply predicted by responses to single gratings presented alone. This complexity is surprising, since excitatory neurons in V1 are considered to be mainly tuned to single preferred orientations. Here we examined the consequences for visual processing of two alternative connectivity schemes: in the first case, local connections are aligned with visual properties inherited from feedforward input (a 'like-to-like' scheme specifically connecting neurons that share similar preferred orientations); in the second case, local connections group neurons into excitatory subnetworks that combine and amplify multiple feedforward visual properties (a 'feature binding' scheme). By comparing predictions from large scale computational models with in vivo recordings of visual representations in mouse V1, we found that responses to plaid stimuli were best explained by assuming feature binding connectivity. Unlike under the like-to-like scheme, selective amplification within feature-binding excitatory subnetworks replicated experimentally observed facilitatory responses to plaid stimuli; explained selective plaid responses not predicted by grating selectivity; and was consistent with broad anatomical selectivity observed in mouse V1. Our results show that visual feature binding can occur through local recurrent mechanisms without requiring feedforward convergence, and that such a mechanism is consistent with visual responses and cortical anatomy in mouse V1.
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http://dx.doi.org/10.1371/journal.pcbi.1005888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746254PMC
December 2017

Neocortical dynamics during whisker-based sensory discrimination in head-restrained mice.

Neuroscience 2018 Jan 14;368:57-69. Epub 2017 Sep 14.

Laboratory of Neural Circuit Dynamics, Brain Research Institute, University of Zurich, Switzerland.

A fundamental task frequently encountered by brains is to rapidly and reliably discriminate between sensory stimuli of the same modality, be it distinct auditory sounds, odors, visual patterns, or tactile textures. A key mammalian brain structure involved in discrimination behavior is the neocortex. Sensory processing not only involves the respective primary sensory area, which is crucial for perceptual detection, but additionally relies on cortico-cortical communication among several regions including higher-order sensory areas as well as frontal cortical areas. It remains elusive how these regions exchange information to process neural representations of distinct stimuli to bring about a decision and initiate appropriate behavioral responses. Likewise, it is poorly understood how these neural computations are conjured during task learning. In this review, we discuss recent studies investigating cortical dynamics during discrimination behaviors that utilize head-fixed behavioral tasks in combination with in vivo electrophysiology, two-photon calcium imaging, and cell-type-specific targeting. We particularly focus on information flow in distinct cortico-cortical pathways when mice use their whiskers to discriminate between different objects or different locations. Within the primary and secondary somatosensory cortices (S1 and S2, respectively) as well as vibrissae motor cortex (M1), intermingled functional representations of touch, whisking, and licking were found, which partially re-organized during discrimination learning. These findings provide first glimpses of cortico-cortical communication but emphasize that for understanding the complete process of discrimination it will be crucial to elucidate the details of how neural processing is coordinated across brain-wide neuronal networks including the S1-S2-M1 triangle and cortical areas beyond.
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http://dx.doi.org/10.1016/j.neuroscience.2017.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726900PMC
January 2018

Multiphoton in vivo imaging with a femtosecond semiconductor disk laser.

Biomed Opt Express 2017 Jul 13;8(7):3213-3231. Epub 2017 Jun 13.

Department of Physics, Institute for Quantum Electronics, ETH Zurich, 8093 Zürich, Switzerland.

We use an ultrafast diode-pumped semiconductor disk laser (SDL) to demonstrate several applications in multiphoton microscopy. The ultrafast SDL is based on an optically pumped Vertical External Cavity Surface Emitting Laser (VECSEL) passively mode-locked with a semiconductor saturable absorber mirror (SESAM) and generates 170-fs pulses at a center wavelength of 1027 nm with a repetition rate of 1.63 GHz. We demonstrate the suitability of this laser for structural and functional multiphoton imaging in both larvae and mice for a variety of fluorophores (including mKate2, tdTomato, Texas Red, OGB-1, and R-CaMP1.07) and for endogenous second-harmonic generation in muscle cell sarcomeres. We can demonstrate equivalent signal levels compared to a standard 80-MHz Ti:Sapphire laser when we increase the average power by a factor of 4.5 as predicted by theory. In addition, we compare the bleaching properties of both laser systems in fixed Drosophila larvae and find similar bleaching kinetics despite the large difference in pulse repetition rates. Our results highlight the great potential of ultrafast diode-pumped SDLs for creating a cost-efficient and compact alternative light source compared to standard Ti:Sapphire lasers for multiphoton imaging.
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http://dx.doi.org/10.1364/BOE.8.003213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508824PMC
July 2017