Publications by authors named "Sonja B Hofer"

30 Publications

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Flexible inhibitory control of visually evoked defensive behavior by the ventral lateral geniculate nucleus.

Neuron 2021 Oct 4. Epub 2021 Oct 4.

Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, UK. Electronic address:

Animals can choose to act upon, or to ignore, sensory stimuli, depending on circumstance and prior knowledge. This flexibility is thought to depend on neural inhibition, through suppression of inappropriate and disinhibition of appropriate actions. Here, we identified the ventral lateral geniculate nucleus (vLGN), an inhibitory prethalamic area, as a critical node for control of visually evoked defensive responses in mice. The activity of vLGN projections to the medial superior colliculus (mSC) is modulated by previous experience of threatening stimuli, tracks the perceived threat level in the environment, and is low prior to escape from a visual threat. Optogenetic stimulation of the vLGN abolishes escape responses, and suppressing its activity lowers the threshold for escape and increases risk-avoidance behavior. The vLGN most strongly affects visual threat responses, potentially via modality-specific inhibition of mSC circuits. Thus, inhibitory vLGN circuits control defensive behavior, depending on an animal's prior experience and its anticipation of danger in the environment.
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http://dx.doi.org/10.1016/j.neuron.2021.09.003DOI Listing
October 2021

A database and deep learning toolbox for noise-optimized, generalized spike inference from calcium imaging.

Nat Neurosci 2021 09 2;24(9):1324-1337. Epub 2021 Aug 2.

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

Inference of action potentials ('spikes') from neuronal calcium signals is complicated by the scarcity of simultaneous measurements of action potentials and calcium signals ('ground truth'). In this study, we compiled a large, diverse ground truth database from publicly available and newly performed recordings in zebrafish and mice covering a broad range of calcium indicators, cell types and signal-to-noise ratios, comprising a total of more than 35 recording hours from 298 neurons. We developed an algorithm for spike inference (termed CASCADE) that is based on supervised deep networks, takes advantage of the ground truth database, infers absolute spike rates and outperforms existing model-based algorithms. To optimize performance for unseen imaging data, CASCADE retrains itself by resampling ground truth data to match the respective sampling rate and noise level; therefore, no parameters need to be adjusted by the user. In addition, we developed systematic performance assessments for unseen data, openly released a resource toolbox and provide a user-friendly cloud-based implementation.
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http://dx.doi.org/10.1038/s41593-021-00895-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611618PMC
September 2021

Standardized and reproducible measurement of decision-making in mice.

Elife 2021 05 20;10. Epub 2021 May 20.

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

Progress in science requires standardized assays whose results can be readily shared, compared, and reproduced across laboratories. Reproducibility, however, has been a concern in neuroscience, particularly for measurements of mouse behavior. Here, we show that a standardized task to probe decision-making in mice produces reproducible results across multiple laboratories. We adopted a task for head-fixed mice that assays perceptual and value-based decision making, and we standardized training protocol and experimental hardware, software, and procedures. We trained 140 mice across seven laboratories in three countries, and we collected 5 million mouse choices into a publicly available database. Learning speed was variable across mice and laboratories, but once training was complete there were no significant differences in behavior across laboratories. Mice in different laboratories adopted similar reliance on visual stimuli, on past successes and failures, and on estimates of stimulus prior probability to guide their choices. These results reveal that a complex mouse behavior can be reproduced across multiple laboratories. They establish a standard for reproducible rodent behavior, and provide an unprecedented dataset and open-access tools to study decision-making in mice. More generally, they indicate a path toward achieving reproducibility in neuroscience through collaborative open-science approaches.
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http://dx.doi.org/10.7554/eLife.63711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137147PMC
May 2021

Visual intracortical and transthalamic pathways carry distinct information to cortical areas.

Neuron 2021 06 11;109(12):1996-2008.e6. Epub 2021 May 11.

Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, UK; Biozentrum, University of Basel, Basel, Switzerland. Electronic address:

Sensory processing involves information flow between neocortical areas, assumed to rely on direct intracortical projections. However, cortical areas may also communicate indirectly via higher-order nuclei in the thalamus, such as the pulvinar or lateral posterior nucleus (LP) in the visual system of rodents. The fine-scale organization and function of these cortico-thalamo-cortical pathways remains unclear. We find that responses of mouse LP neurons projecting to higher visual areas likely derive from feedforward input from primary visual cortex (V1) combined with information from many cortical and subcortical areas, including superior colliculus. Signals from LP projections to different higher visual areas are tuned to specific features of visual stimuli and their locomotor context, distinct from the signals carried by direct intracortical projections from V1. Thus, visual transthalamic pathways are functionally specific to their cortical target, different from feedforward cortical pathways, and combine information from multiple brain regions, linking sensory signals with behavioral context.
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http://dx.doi.org/10.1016/j.neuron.2021.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221812PMC
June 2021

Contextual signals in visual cortex.

Curr Opin Neurobiol 2018 10 5;52:131-138. Epub 2018 Jun 5.

Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, UK. Electronic address:

Vision is an active process. What we perceive strongly depends on our actions, intentions and expectations. During visual processing, these internal signals therefore need to be integrated with the visual information from the retina. The mechanisms of how this is achieved by the visual system are still poorly understood. Advances in recording and manipulating neuronal activity in specific cell types and axonal projections together with tools for circuit tracing are beginning to shed light on the neuronal circuit mechanisms of how internal, contextual signals shape sensory representations. Here we review recent work, primarily in mice, that has advanced our understanding of these processes, focusing on contextual signals related to locomotion, behavioural relevance and predictions.
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http://dx.doi.org/10.1016/j.conb.2018.05.003DOI Listing
October 2018

Distinct learning-induced changes in stimulus selectivity and interactions of GABAergic interneuron classes in visual cortex.

Nat Neurosci 2018 06 21;21(6):851-859. Epub 2018 May 21.

Biozentrum, University of Basel, Basel, Switzerland.

How learning enhances neural representations for behaviorally relevant stimuli via activity changes of cortical cell types remains unclear. We simultaneously imaged responses of pyramidal cells (PYR) along with parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP) inhibitory interneurons in primary visual cortex while mice learned to discriminate visual patterns. Learning increased selectivity for task-relevant stimuli of PYR, PV and SOM subsets but not VIP cells. Strikingly, PV neurons became as selective as PYR cells, and their functional interactions reorganized, leading to the emergence of stimulus-selective PYR-PV ensembles. Conversely, SOM activity became strongly decorrelated from the network, and PYR-SOM coupling before learning predicted selectivity increases in individual PYR cells. Thus, learning differentially shapes the activity and interactions of multiple cell classes: while SOM inhibition may gate selectivity changes, PV interneurons become recruited into stimulus-specific ensembles and provide more selective inhibition as the network becomes better at discriminating behaviorally relevant stimuli.
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http://dx.doi.org/10.1038/s41593-018-0143-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390950PMC
June 2018

Synaptic organization of visual space in primary visual cortex.

Nature 2017 07 12;547(7664):449-452. Epub 2017 Jul 12.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.

How a sensory stimulus is processed and perceived depends on the surrounding sensory scene. In the visual cortex, contextual signals can be conveyed by an extensive network of intra- and inter-areal excitatory connections that link neurons representing stimulus features separated in visual space. However, the connectional logic of visual contextual inputs remains unknown; it is not clear what information individual neurons receive from different parts of the visual field, nor how this input relates to the visual features that a neuron encodes, defined by its spatial receptive field. Here we determine the organization of excitatory synaptic inputs responding to different locations in the visual scene by mapping spatial receptive fields in dendritic spines of mouse visual cortex neurons using two-photon calcium imaging. We find that neurons receive functionally diverse inputs from extended regions of visual space. Inputs representing similar visual features from the same location in visual space are more likely to cluster on neighbouring spines. Inputs from visual field regions beyond the receptive field of the postsynaptic neuron often synapse on higher-order dendritic branches. These putative long-range inputs are more frequent and more likely to share the preference for oriented edges with the postsynaptic neuron when the receptive field of the input is spatially displaced along the axis of the receptive field orientation of the postsynaptic neuron. Therefore, the connectivity between neurons with displaced receptive fields obeys a specific rule, whereby they connect preferentially when their receptive fields are co-oriented and co-axially aligned. This organization of synaptic connectivity is ideally suited for the amplification of elongated edges, which are enriched in the visual environment, and thus provides a potential substrate for contour integration and object grouping.
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http://dx.doi.org/10.1038/nature23019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533220PMC
July 2017

Ferret Interneurons Defy Expectations.

Neuron 2017 Mar;93(5):985-987

Biozentrum, University of Basel, 4056 Basel, Switzerland. Electronic address:

Parvalbumin interneurons in the cortex are believed to pool inputs from most surrounding excitatory cells independent of their functional properties. Response properties of interneurons in columnar visual cortex of ferrets, described by Wilson et al. (2017) in this issue of Neuron, challenge this view.
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http://dx.doi.org/10.1016/j.neuron.2017.02.037DOI Listing
March 2017

Model Constrained by Visual Hierarchy Improves Prediction of Neural Responses to Natural Scenes.

PLoS Comput Biol 2016 06 27;12(6):e1004927. Epub 2016 Jun 27.

Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.

Accurate estimation of neuronal receptive fields is essential for understanding sensory processing in the early visual system. Yet a full characterization of receptive fields is still incomplete, especially with regard to natural visual stimuli and in complete populations of cortical neurons. While previous work has incorporated known structural properties of the early visual system, such as lateral connectivity, or imposing simple-cell-like receptive field structure, no study has exploited the fact that nearby V1 neurons share common feed-forward input from thalamus and other upstream cortical neurons. We introduce a new method for estimating receptive fields simultaneously for a population of V1 neurons, using a model-based analysis incorporating knowledge of the feed-forward visual hierarchy. We assume that a population of V1 neurons shares a common pool of thalamic inputs, and consists of two layers of simple and complex-like V1 neurons. When fit to recordings of a local population of mouse layer 2/3 V1 neurons, our model offers an accurate description of their response to natural images and significant improvement of prediction power over the current state-of-the-art methods. We show that the responses of a large local population of V1 neurons with locally diverse receptive fields can be described with surprisingly limited number of thalamic inputs, consistent with recent experimental findings. Our structural model not only offers an improved functional characterization of V1 neurons, but also provides a framework for studying the relationship between connectivity and function in visual cortical areas.
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http://dx.doi.org/10.1371/journal.pcbi.1004927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922657PMC
June 2016

Thalamic nuclei convey diverse contextual information to layer 1 of visual cortex.

Nat Neurosci 2016 Feb 21;19(2):299-307. Epub 2015 Dec 21.

Biozentrum, University of Basel, Switzerland.

Sensory perception depends on the context in which a stimulus occurs. Prevailing models emphasize cortical feedback as the source of contextual modulation. However, higher order thalamic nuclei, such as the pulvinar, interconnect with many cortical and subcortical areas, suggesting a role for the thalamus in providing sensory and behavioral context. Yet the nature of the signals conveyed to cortex by higher order thalamus remains poorly understood. Here we use axonal calcium imaging to measure information provided to visual cortex by the pulvinar equivalent in mice, the lateral posterior nucleus (LP), as well as the dorsolateral geniculate nucleus (dLGN). We found that dLGN conveys retinotopically precise visual signals, while LP provides distributed information from the visual scene. Both LP and dLGN projections carry locomotion signals. However, while dLGN inputs often respond to positive combinations of running and visual flow speed, LP signals discrepancies between self-generated and external visual motion. This higher order thalamic nucleus therefore conveys diverse contextual signals that inform visual cortex about visual scene changes not predicted by the animal's own actions.
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http://dx.doi.org/10.1038/nn.4197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480596PMC
February 2016

Learning Enhances Sensory and Multiple Non-sensory Representations in Primary Visual Cortex.

Neuron 2015 Jun 4;86(6):1478-90. Epub 2015 Jun 4.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland; University College London, 21 University Street, London WC1E 6DE, UK. Electronic address:

We determined how learning modifies neural representations in primary visual cortex (V1) during acquisition of a visually guided behavioral task. We imaged the activity of the same layer 2/3 neuronal populations as mice learned to discriminate two visual patterns while running through a virtual corridor, where one pattern was rewarded. Improvements in behavioral performance were closely associated with increasingly distinguishable population-level representations of task-relevant stimuli, as a result of stabilization of existing and recruitment of new neurons selective for these stimuli. These effects correlated with the appearance of multiple task-dependent signals during learning: those that increased neuronal selectivity across the population when expert animals engaged in the task, and those reflecting anticipation or behavioral choices specifically in neuronal subsets preferring the rewarded stimulus. Therefore, learning engages diverse mechanisms that modify sensory and non-sensory representations in V1 to adjust its processing to task requirements and the behavioral relevance of visual stimuli.
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http://dx.doi.org/10.1016/j.neuron.2015.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503798PMC
June 2015

Diverse coupling of neurons to populations in sensory cortex.

Nature 2015 May 6;521(7553):511-515. Epub 2015 Apr 6.

Dept. of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6DE.

A large population of neurons can, in principle, produce an astronomical number of distinct firing patterns. In cortex, however, these patterns lie in a space of lower dimension, as if individual neurons were "obedient members of a huge orchestra". Here we use recordings from the visual cortex of mouse (Mus musculus) and monkey (Macaca mulatta) to investigate the relationship between individual neurons and the population, and to establish the underlying circuit mechanisms. We show that neighbouring neurons can differ in their coupling to the overall firing of the population, ranging from strongly coupled 'choristers' to weakly coupled 'soloists'. Population coupling is largely independent of sensory preferences, and it is a fixed cellular attribute, invariant to stimulus conditions. Neurons with high population coupling are more strongly affected by non-sensory behavioural variables such as motor intention. Population coupling reflects a causal relationship, predicting the response of a neuron to optogenetically driven increases in local activity. Moreover, population coupling indicates synaptic connectivity; the population coupling of a neuron, measured in vivo, predicted subsequent in vitro estimates of the number of synapses received from its neighbours. Finally, population coupling provides a compact summary of population activity; knowledge of the population couplings of n neurons predicts a substantial portion of their n(2) pairwise correlations. Population coupling therefore represents a novel, simple measure that characterizes the relationship of each neuron to a larger population, explaining seemingly complex network firing patterns in terms of basic circuit variables.
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http://dx.doi.org/10.1038/nature14273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449271PMC
May 2015

Functional organization of excitatory synaptic strength in primary visual cortex.

Nature 2015 Feb 4;518(7539):399-403. Epub 2015 Feb 4.

Department of Neuroscience, Physiology and Pharmacology, University College London, 21 University Street, London WC1E 6DE, UK.

The strength of synaptic connections fundamentally determines how neurons influence each other's firing. Excitatory connection amplitudes between pairs of cortical neurons vary over two orders of magnitude, comprising only very few strong connections among many weaker ones. Although this highly skewed distribution of connection strengths is observed in diverse cortical areas, its functional significance remains unknown: it is not clear how connection strength relates to neuronal response properties, nor how strong and weak inputs contribute to information processing in local microcircuits. Here we reveal that the strength of connections between layer 2/3 (L2/3) pyramidal neurons in mouse primary visual cortex (V1) obeys a simple rule--the few strong connections occur between neurons with most correlated responses, while only weak connections link neurons with uncorrelated responses. Moreover, we show that strong and reciprocal connections occur between cells with similar spatial receptive field structure. Although weak connections far outnumber strong connections, each neuron receives the majority of its local excitation from a small number of strong inputs provided by the few neurons with similar responses to visual features. By dominating recurrent excitation, these infrequent yet powerful inputs disproportionately contribute to feature preference and selectivity. Therefore, our results show that the apparently complex organization of excitatory connection strength reflects the similarity of neuronal responses, and suggest that rare, strong connections mediate stimulus-specific response amplification in cortical microcircuits.
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http://dx.doi.org/10.1038/nature14182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843963PMC
February 2015

Emergence of feature-specific connectivity in cortical microcircuits in the absence of visual experience.

J Neurosci 2014 Jul;34(29):9812-6

Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6DE, United Kingdom, and Biozentrum, University of Basel, 4056 Basel, Switzerland

In primary visual cortex (V1), connectivity between layer 2/3 (L2/3) excitatory neurons undergoes extensive reorganization after the onset of visual experience whereby neurons with similar feature selectivity form functional microcircuits (Ko et al., 2011, 2013). It remains unknown whether visual experience is required for the developmental refinement of intracortical circuitry or whether this maturation is guided intrinsically. Here, we correlated the connectivity between V1 L2/3 neurons assayed by simultaneous whole-cell recordings in vitro to their response properties measured by two-photon calcium imaging in vivo in dark-reared mice. We found that neurons with similar responses to oriented gratings or natural movies became preferentially connected in the absence of visual experience. However, the relationship between connectivity and similarity of visual responses to natural movies was not as strong in dark-reared as in normally reared mice. Moreover, dark rearing prevented the normally occurring loss of connections between visually nonresponsive neurons after eye opening (Ko et al., 2013). Therefore, our data suggest that the absence of visual input does not prevent the emergence of functionally specific recurrent connectivity in cortical circuits; however, visual experience is required for complete microcircuit maturation.
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http://dx.doi.org/10.1523/JNEUROSCI.0875-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4099553PMC
July 2014

The emergence of functional microcircuits in visual cortex.

Nature 2013 Apr;496(7443):96-100

Department of Neuroscience, Physiology and Pharmacology, University College London, 21 University Street, London WC1E 6DE, UK.

Sensory processing occurs in neocortical microcircuits in which synaptic connectivity is highly structured and excitatory neurons form subnetworks that process related sensory information. However, the developmental mechanisms underlying the formation of functionally organized connectivity in cortical microcircuits remain unknown. Here we directly relate patterns of excitatory synaptic connectivity to visual response properties of neighbouring layer 2/3 pyramidal neurons in mouse visual cortex at different postnatal ages, using two-photon calcium imaging in vivo and multiple whole-cell recordings in vitro. Although neural responses were already highly selective for visual stimuli at eye opening, neurons responding to similar visual features were not yet preferentially connected, indicating that the emergence of feature selectivity does not depend on the precise arrangement of local synaptic connections. After eye opening, local connectivity reorganized extensively: more connections formed selectively between neurons with similar visual responses and connections were eliminated between visually unresponsive neurons, but the overall connectivity rate did not change. We propose a sequential model of cortical microcircuit development based on activity-dependent mechanisms of plasticity whereby neurons first acquire feature preference by selecting feedforward inputs before the onset of sensory experience--a process that may be facilitated by early electrical coupling between neuronal subsets--and then patterned input drives the formation of functional subnetworks through a redistribution of recurrent synaptic connections.
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http://dx.doi.org/10.1038/nature12015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843961PMC
April 2013

Elimination of inhibitory synapses is a major component of adult ocular dominance plasticity.

Neuron 2012 Apr;74(2):374-83

Department of Molecular Visual Plasticity, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.

During development, cortical plasticity is associated with the rearrangement of excitatory connections. While these connections become more stable with age, plasticity can still be induced in the adult cortex. Here we provide evidence that structural plasticity of inhibitory synapses onto pyramidal neurons is a major component of plasticity in the adult neocortex. In vivo two-photon imaging was used to monitor the formation and elimination of fluorescently labeled inhibitory structures on pyramidal neurons. We find that ocular dominance plasticity in the adult visual cortex is associated with rapid inhibitory synapse loss, especially of those present on dendritic spines. This occurs not only with monocular deprivation but also with subsequent restoration of binocular vision. We propose that in the adult visual cortex the experience-induced loss of inhibition may effectively strengthen specific visual inputs with limited need for rearranging the excitatory circuitry.
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http://dx.doi.org/10.1016/j.neuron.2012.03.015DOI Listing
April 2012

Differential connectivity and response dynamics of excitatory and inhibitory neurons in visual cortex.

Nat Neurosci 2011 Jul 17;14(8):1045-52. Epub 2011 Jul 17.

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

Neuronal responses during sensory processing are influenced by both the organization of intracortical connections and the statistical features of sensory stimuli. How these intrinsic and extrinsic factors govern the activity of excitatory and inhibitory populations is unclear. Using two-photon calcium imaging in vivo and intracellular recordings in vitro, we investigated the dependencies between synaptic connectivity, feature selectivity and network activity in pyramidal cells and fast-spiking parvalbumin-expressing (PV) interneurons in mouse visual cortex. In pyramidal cell populations, patterns of neuronal correlations were largely stimulus-dependent, indicating that their responses were not strongly dominated by functionally biased recurrent connectivity. By contrast, visual stimulation only weakly modified co-activation patterns of fast-spiking PV cells, consistent with the observation that these broadly tuned interneurons received very dense and strong synaptic input from nearby pyramidal cells with diverse feature selectivities. Therefore, feedforward and recurrent network influences determine the activity of excitatory and inhibitory ensembles in fundamentally different ways.
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http://dx.doi.org/10.1038/nn.2876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370002PMC
July 2011

Functional specificity of local synaptic connections in neocortical networks.

Nature 2011 May 10;473(7345):87-91. Epub 2011 Apr 10.

Department of Neuroscience, Physiology and Pharmacology, University College London, 21 University Street, London WC1E 6DE, UK.

Neuronal connectivity is fundamental to information processing in the brain. Therefore, understanding the mechanisms of sensory processing requires uncovering how connection patterns between neurons relate to their function. On a coarse scale, long-range projections can preferentially link cortical regions with similar responses to sensory stimuli. But on the local scale, where dendrites and axons overlap substantially, the functional specificity of connections remains unknown. Here we determine synaptic connectivity between nearby layer 2/3 pyramidal neurons in vitro, the response properties of which were first characterized in mouse visual cortex in vivo. We found that connection probability was related to the similarity of visually driven neuronal activity. Neurons with the same preference for oriented stimuli connected at twice the rate of neurons with orthogonal orientation preferences. Neurons responding similarly to naturalistic stimuli formed connections at much higher rates than those with uncorrelated responses. Bidirectional synaptic connections were found more frequently between neuronal pairs with strongly correlated visual responses. Our results reveal the degree of functional specificity of local synaptic connections in the visual cortex, and point to the existence of fine-scale subnetworks dedicated to processing related sensory information.
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http://dx.doi.org/10.1038/nature09880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089591PMC
May 2011

Optimization of population decoding with distance metrics.

Neural Netw 2010 Aug 5;23(6):728-32. Epub 2010 May 5.

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

Recent advances in multi-electrode recording and imaging techniques have made it possible to observe the activity of large populations of neurons. However, to take full advantage of these techniques, new methods for the analysis of population responses must be developed. In this paper, we present an algorithm for optimizing population decoding with distance metrics. To demonstrate the utility of this algorithm under experimental conditions, we evaluate its performance in decoding both population spike trains and calcium signals with different correlation structures. Our results demonstrate that the optimized decoder outperforms other simple population decoders and suggest that optimization could serve as a tool for quantifying the potential contribution of individual cells to the population code.
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http://dx.doi.org/10.1016/j.neunet.2010.04.007DOI Listing
August 2010

Dendritic spines: the stuff that memories are made of?

Curr Biol 2010 Feb;20(4):R157-9

Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1 6JJ, UK.

Two new studies explore structural changes of nerve cells as a potential mechanism for memory formation by studying synaptic reorganization associated with motor learning.
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http://dx.doi.org/10.1016/j.cub.2009.12.040DOI Listing
February 2010

Structural traces of past experience in the cerebral cortex.

Authors:
Sonja B Hofer

J Mol Med (Berl) 2010 Mar 11;88(3):235-9. Epub 2009 Nov 11.

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

It is widely assumed that changes in the connections between neurons mediate the integration and storage of information in the brain and thereby underlie our ability to learn and remember. In particular, long-term memory is thought to rely on a structural reorganisation of neuronal circuits, but the proof for such a mechanism in the complex mammalian brain remains elusive. Recent advances in scientists' ability to follow structural dynamics of neuronal networks in the intact brain in vivo by means of 2-photon laser scanning microscopy has provided new insight into how information about new experiences might be stored in brain circuits.
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http://dx.doi.org/10.1007/s00109-009-0560-2DOI Listing
March 2010

Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window.

Nat Protoc 2009 16;4(8):1128-44. Epub 2009 Jul 16.

Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.

To understand the cellular and circuit mechanisms of experience-dependent plasticity, neurons and their synapses need to be studied in the intact brain over extended periods of time. Two-photon excitation laser scanning microscopy (2PLSM), together with expression of fluorescent proteins, enables high-resolution imaging of neuronal structure in vivo. In this protocol we describe a chronic cranial window to obtain optical access to the mouse cerebral cortex for long-term imaging. A small bone flap is replaced with a coverglass, which is permanently sealed in place with dental acrylic, providing a clear imaging window with a large field of view (approximately 0.8-12 mm(2)). The surgical procedure can be completed within approximately 1 h. The preparation allows imaging over time periods of months with arbitrary imaging intervals. The large size of the imaging window facilitates imaging of ongoing structural plasticity of small neuronal structures in mice, with low densities of labeled neurons. The entire dendritic and axonal arbor of individual neurons can be reconstructed.
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http://dx.doi.org/10.1038/nprot.2009.89DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072839PMC
December 2009

A genetically encoded calcium indicator for chronic in vivo two-photon imaging.

Nat Methods 2008 Sep;5(9):805-11

Max Planck Institute of Neurobiology, Am Klopferspitz 18, D-82152 Martinsried, Germany.

Neurons in the nervous system can change their functional properties over time. At present, there are no techniques that allow reliable monitoring of changes within identified neurons over repeated experimental sessions. We increased the signal strength of troponin C-based calcium biosensors in the low-calcium regime by mutagenesis and domain rearrangement within the troponin C calcium binding moiety to generate the indicator TN-XXL. Using in vivo two-photon ratiometric imaging, we show that TN-XXL exhibits enhanced fluorescence changes in neurons of flies and mice. TN-XXL could be used to obtain tuning curves of orientation-selective neurons in mouse visual cortex measured repeatedly over days and weeks. Thus, the genetically encoded calcium indicator TN-XXL allows repeated imaging of response properties from individual, identified neurons in vivo, which will be crucial for gaining new insights into cellular mechanisms of plasticity, regeneration and disease.
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http://dx.doi.org/10.1038/nmeth.1243DOI Listing
September 2008

Experience leaves a lasting structural trace in cortical circuits.

Nature 2009 Jan 12;457(7227):313-7. Epub 2008 Nov 12.

Max Planck Institute of Neurobiology, D-82152 Martinsried, Germany.

Sensory experiences exert a powerful influence on the function and future performance of neuronal circuits in the mammalian neocortex. Restructuring of synaptic connections is believed to be one mechanism by which cortical circuits store information about the sensory world. Excitatory synaptic structures, such as dendritic spines, are dynamic entities that remain sensitive to alteration of sensory input throughout life. It remains unclear, however, whether structural changes at the level of dendritic spines can outlast the original experience and thereby provide a morphological basis for long-term information storage. Here we follow spine dynamics on apical dendrites of pyramidal neurons in functionally defined regions of adult mouse visual cortex during plasticity of eye-specific responses induced by repeated closure of one eye (monocular deprivation). The first monocular deprivation episode doubled the rate of spine formation, thereby increasing spine density. This effect was specific to layer-5 cells located in binocular cortex, where most neurons increase their responsiveness to the non-deprived eye. Restoring binocular vision returned spine dynamics to baseline levels, but absolute spine density remained elevated and many monocular deprivation-induced spines persisted during this period of functional recovery. However, spine addition did not increase again when the same eye was closed for a second time. This absence of structural plasticity stands out against the robust changes of eye-specific responses that occur even faster after repeated deprivation. Thus, spines added during the first monocular deprivation experience may provide a structural basis for subsequent functional shifts. These results provide a strong link between functional plasticity and specific synaptic rearrangements, revealing a mechanism of how prior experiences could be stored in cortical circuits.
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http://dx.doi.org/10.1038/nature07487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485433PMC
January 2009

Cre-dependent expression of multiple transgenes in isolated neurons of the adult forebrain.

PLoS One 2008 Aug 26;3(8):e3059. Epub 2008 Aug 26.

Molecular Visual Plasticity Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.

Background: Transgenic mice with mosaic, Golgi-staining-like expression of enhanced green fluorescent protein (EGFP) have been very useful in studying the dynamics of neuronal structure and function. In order to further investigate the molecular events regulating structural plasticity, it would be useful to express multiple proteins in the same sparse neurons, allowing co-expression of functional proteins or co-labeling of subcellular compartments with other fluorescent proteins. However, it has been difficult to obtain reproducible expression in the same subset of neurons for direct comparison of neurons expressing different functional proteins.

Principal Findings: Here we describe a Cre-transgenic line that allows reproducible expression of transgenic proteins of choice in a small number of neurons of the adult cortex, hippocampus, striatum, olfactory bulb, subiculum, hypothalamus, superior colliculus and amygdala. We show that using these Cre-transgenic mice, multiple Cre-dependent transgenes can be expressed together in the same isolated neurons. We also describe a Cre-dependent transgenic line expressing a membrane associated EGFP (EGFP-F). Crossed with the Cre-transgenic line, EGFP-F expression starts in the adolescent forebrain, is present in dendrites, dendritic protrusions, axons and boutons and is strong enough for acute or chronic in vivo imaging.

Significance: This triple transgenic approach will aid the morphological and functional characterization of neurons in various Cre-dependent transgenic mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0003059PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518110PMC
August 2008

Homeostatic regulation of eye-specific responses in visual cortex during ocular dominance plasticity.

Neuron 2007 Jun;54(6):961-72

Department of Cellular and Systems Neurobiology, Max Planck Institute of Neurobiology, D-82152 Martinsried, Germany.

Experience-dependent plasticity is crucial for the precise formation of neuronal connections during development. It is generally thought to depend on Hebbian forms of synaptic plasticity. In addition, neurons possess other, homeostatic means of compensating for changes in sensory input, but their role in cortical plasticity is unclear. We used two-photon calcium imaging to investigate whether homeostatic response regulation contributes to changes of eye-specific responsiveness after monocular deprivation (MD) in mouse visual cortex. Short MD durations decreased deprived-eye responses in neurons with binocular input. Longer MD periods strengthened open-eye responses, and surprisingly, also increased deprived-eye responses in neurons devoid of open-eye input. These bidirectional response adjustments effectively preserved the net visual drive for each neuron. Our finding that deprived-eye responses were either weaker or stronger after MD, depending on the amount of open-eye input a cell received, argues for both Hebbian and homeostatic mechanisms regulating neuronal responsiveness during experience-dependent plasticity.
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http://dx.doi.org/10.1016/j.neuron.2007.05.028DOI Listing
June 2007

Lifelong learning: ocular dominance plasticity in mouse visual cortex.

Curr Opin Neurobiol 2006 Aug 11;16(4):451-9. Epub 2006 Jul 11.

Max-Planck-Institut für Neurobiologie, Am Klopferspitz 18, 82152 Martinsried, Germany.

Ocular dominance plasticity has long served as a successful model for examining how cortical circuits are shaped by experience. In this paradigm, altered retinal activity caused by unilateral eye-lid closure leads to dramatic shifts in the binocular response properties of neurons in the visual cortex. Much of the recent progress in identifying the cellular and molecular mechanisms underlying ocular dominance plasticity has been achieved by using the mouse as a model system. In this species, monocular deprivation initiated in adulthood also causes robust ocular dominance shifts. Research on ocular dominance plasticity in the mouse is starting to provide insight into which factors mediate and influence cortical plasticity in juvenile and adult animals.
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http://dx.doi.org/10.1016/j.conb.2006.06.007DOI Listing
August 2006

Prior experience enhances plasticity in adult visual cortex.

Nat Neurosci 2006 Jan 4;9(1):127-32. Epub 2005 Dec 4.

Max-Planck-Institut für Neurobiologie, Am Klopferspitz 18, D-82152 Martinsried, Germany.

The brain has a remarkable capacity to adapt to alterations in its sensory environment, which is normally much more pronounced in juvenile animals. Here we show that in adult mice, the ability to adapt to changes can be improved profoundly if the mouse has already experienced a similar change in its sensory environment earlier in life. Using the standard model for sensory plasticity in mouse visual cortex-ocular dominance (OD) plasticity-we found that a transient shift in OD, induced by monocular deprivation (MD) earlier in life, renders the adult visual cortex highly susceptible to subsequent MD many weeks later. Irrespective of whether the first MD was experienced during the critical period (around postnatal day 28) or in adulthood, OD shifts induced by a second MD were faster, more persistent and specific to repeated deprivation of the same eye. The capacity for plasticity in the mammalian cortex can therefore be conditioned by past experience.
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http://dx.doi.org/10.1038/nn1610DOI Listing
January 2006

Altered map of visual space in the superior colliculus of mice lacking early retinal waves.

J Neurosci 2005 Jul;25(29):6921-8

Max-Planck-Institut für Neurobiologie, D-82152 Martinsried, Germany.

During the development of the mammalian retinocollicular projection, a coarse retinotopic map is set up by the graded distribution of axon guidance molecules. Subsequent refinement of the initially diffuse projection has been shown to depend on the spatially correlated firing of retinal ganglion cells. In this scheme, the abolition of patterned retinal activity is not expected to influence overall retinotopic organization, but this has not been investigated. We used optical imaging of intrinsic signals to visualize the complete retinotopic map in the superior colliculus (SC) of mice lacking early retinal waves, caused by the deletion of the beta2 subunit of the nicotinic acetylcholine receptor. As expected from previous anatomical studies in the SC of beta2(-/-) mice, regions activated by individual visual stimuli were much larger and had less sharp borders than those in wild-type mice. Importantly, however, we also found systematic distortions of the entire retinotopic map: the map of visual space was expanded anteriorly and compressed posteriorly. Thus, patterned neuronal activity in the early retina has a substantial influence on the coarse retinotopic organization of the SC.
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http://dx.doi.org/10.1523/JNEUROSCI.1555-05.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6725344PMC
July 2005

Within- and across-channel processing in auditory masking: a physiological study in the songbird forebrain.

J Neurosci 2003 Jul;23(13):5732-9

Technische Universität München, Lehrstuhl für Zoologie, 85748 Garching, Germany.

Synchronous envelope fluctuations in different frequency ranges of an acoustic background enhance the detection of signals in background noise. This effect, termed comodulation masking release (CMR), is attributed to both processing within one frequency channel of the auditory system and comparisons across separate frequency channels. Here we present data on CMR from a study in field L2 of the auditory forebrain of the European starling (Sturnus vulgaris) using two 25-Hz-wide bands of masking noise that provide the opportunity to distinguish between within-channel and across-channel effects. Acoustically evoked responses were recorded from unrestrained birds via radio telemetry. The signal was a 800 msec pure tone presented at the most sensitive frequency of the units in a previously determined frequency-tuning curve (FTC). One band of masking noise was centered on the signal frequency while the flanking band of noise was presented either within the limits of the excitatory FTC (i.e., within the same frequency channel as the on-frequency masker) or in the suppression area of the FTC (i.e., in a separate channel). For flanking bands inside the excitatory FTC, signal detection thresholds based on the rate code were lower in noise maskers with identical envelope fluctuations (comodulated) than in maskers with uncorrelated envelopes resulting in a neural CMR of approximately 4-7 dB. For flanking bands inside the suppression areas, the neural CMR was reduced. Although the average neural CMR was below the behaviorally determined CMR, a subsample of between 11 and 26% of the recording sites resembled the behavioral performance.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741263PMC
July 2003
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