Steffen Kandler’s research while affiliated with imec and other places

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Publications (22)


Spatially segregated responses to visuo-tactile stimuli in mouse neocortex during active sensation
  • Preprint

September 2019

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29 Reads

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3 Citations

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S Kandler

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V Bonin

Multisensory integration is key for perception and animal survival yet how information from separate senses is integrated has been debated for decades. In the cortex, information from each sense is first processed in primary sensory areas and then combined in association areas. An alternative hypothesis to this hierarchical model is that primary sensory cortices partake in multisensory encoding. We probed tactile and visual responses in primary somatosensory and visual cortices in awake behaving animals using two-photon calcium imaging from layer 2/3 excitatory neurons. In support of an hierarchical model we found segregation of visual and tactile responses. Tactile stimuli evoked responses in S1 neurons. In striking contrast, V1 neurons failed to respond to tactile stimuli. This was true for passive whisker stimulation and for stimulation during active whisking. Furthermore, responses of V1 neurons to congruent visuo-tactile cues during active exploration, a condition where vision precedes touch, were completely abolished in darkness. The rostro-lateral area of the visual cortex responded to both visual and tactile aspects of the stimuli and may form a substrate for encoding multisensory signals during active exploration. Our results indicate that primary sensory areas mainly encode their primary sense and that the impact of other modalities may be restricted to modulatory effects.


Probing visual and tactile activity in primary sensory cortices during active sensing

September 2019

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37 Reads

Integration of information from multiple senses can enhance processing of weak or ambiguous stimuli. Electrophysiological and functional imaging studies, mainly in humans, point for a role of primary sensory cortices. We leveraged widefield and two-photon calcium imaging in behaving mice to probe tactile activity in primary visual cortex (V1). Unambiguously we found no evidence for tactile signals in V1. This was true for passive whisker deflections and for tactile stimuli presented during active whisking and controlled by animal locomotion.


Figure 1. Distinct Ca 2+ Responses in Astrocytes of the Mouse Visual Cortex during Locomotion and Visual Stimulation
Figure 2. Individual Astrocytes Respond to Visual Stimulation (A) Left: example 2-photon imaging FOV (white square) at the cortical surface. Dashed line indicates V1. Center and right: 2-photon imaging at 160 mm cortical depth. Black and white frames are 1-s averages obtained at indicated times after visual stimulation onset. Position of the stimulus is indicated above. Scale bars, 1 mm for 1-photon FOV, 50 mm for 2-photon FOV. See also Video S3. (B) 2-photon response maps showing time-to-response peak relative to visual stimulus onset. Maps are the average of 10 trials for each direction of motion, recorded from a single animal. The pseudo-color scale is adjusted to match the range of delays observed in responses to the moving bar stimuli. Pixels below a fluorescence threshold are shown in gray. Scale bar, 50 mm. See also Video S3. (C) Cumulative distribution plot showing the amplitudes of locomotion responses (black line, n = 727 events), as compared to activity during preceding stationary epochs (baseline) (gray line, n = 797 events). 7 animals, 133 cells. (D) Cumulative distribution plots showing the amplitudes of responses to visual stimulation (black line, n = 1,733 trials), as compared to pre-stimulus baseline (gray line, n = 533 events). 7 animals, 133 cells. (E) Cumulative distribution plots showing the half-width at half-maximum of responses to visual stimulation obtained with 2-photon (black line, n = 1,129 trials, 133 cells, 7 animals) or 1-photon imaging (gray line, n = 233 trials, 8 animals). See also Figure S1.
Figure 4. Visually Induced and Locomotion-Related Signals Operate through Distinct Mechanisms (A) Noradrenaline depletion abolishes the Ca 2+ responses associated with locomotion onset. Example Ca 2+ transients (top) recorded using 1-photon imaging from an animal during voluntary locomotion (bottom) pre-(left) and post-(right) DSP-4 administration. (B) Example Ca 2+ transients (top) recorded using 1-photon imaging from a mouse during 10 trials of visual stimulation with voluntary locomotion (bottom) pre-(left) and post-(right) DSP-4 administration. (C) Cumulative distribution plots showing the peak fluorescence during periods of stationarity (no movement for 8 s or more; gray curves) and after locomotion onset (black curves, 8-s window) pre-(left, n = 88 events) and post-(right, n = 114 events) DSP-4 administration. Signal from the strongest responders (90% percentile) after locomotion onset was 11.8% dF/F 0 and 1.3% dF/F 0 above baseline fluorescence before or after DSP-4, respectively. (D) Cumulative distribution plots show the peak fluorescence before (gray curves) and after (black curves, 8-s window) visual stimulation onset, pre-(left, n = 318 trials) and post-(right, n = 311 trials) DSP-4 administration. Signal from the strongest responders (90% percentile) during visual stimulation was 15.9% dF/F 0 and 4.7% dF/F 0 above pre-stimulation levels before or after DSP-4, respectively. Activity before visual stimulus onset was measured during an 8-s window irrespective of whether the animals were stationary or locomoting. The analysis window was slid independently to be centered approximate to the response peak (STAR Methods). (E and F) Black and white maps show average activities for vision-induced increases in GCaMP6 fluorescence across trials and stimulus directions. Pseudo-color response maps show the average time to reach maximum GCaMP6 intensity after stimulus onset for the stimulus directions indicated. Maps are the average of 10 trials per stimulus direction in 1 animal pre-(E) and post-(F) DSP-4 administration. Scale bars, 1 mm. See also Figure S4 and Video S4.
Distinct Mechanisms for Visual and Motor-Related Astrocyte Responses in Mouse Visual Cortex
  • Article
  • Full-text available

September 2019

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201 Reads

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54 Citations

Current Biology

Astrocytes are a major cell type in the mammalian nervous system, are in close proximity to neurons, and show rich Ca2+ activity thought to mediate cellular outputs. Astrocytes show activity linked to sensory [1, 2] and motor [3, 4] events, reflecting local neural activity and brain-wide neuromodulatory inputs. Sensory responses are highly variable [5-10], which may reflect interactions between distinct input types [6, 7, 9]. However, the diversity of inputs generating astrocyte activity, particularly during sensory stimulation and behavior, is not fully understood [11, 12]. Using a combination of Ca2+ imaging, a treadmill assay, and visual stimulation, we examined the properties of astrocyte activity in mouse visual cortex associated with motor or sensory events. Consistent with previous work, motor activity activated astrocytes across the cortex with little specificity, reflecting a diffuse neuromodulatory mechanism. In contrast, moving visual stimuli generated specific activity patterns that reflected the stimulus' trajectory within the visual field, precisely as one would predict if astrocytes reported local neural activity. Visual responses depended strongly on behavioral state, with astrocytes showing high amplitude Ca2+ transients during locomotion and little activity during stillness. Furthermore, the amplitudes of visual responses were highly correlated with pupil size, suggesting a role of arousal. Interestingly, while depletion of cortical noradrenaline abolished locomotor responses, visual responses were only reduced in amplitude and their spatiotemporal organization remained intact, suggesting two distinct types of inputs underlie visual responses. We conclude that cortical astrocytes integrate local sensory information and behavioral state, suggesting a role in information processing.

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Astrocytes integrate local sensory and brain-wide neuromodulatory signals

July 2018

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81 Reads

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3 Citations

Astrocytes play multiple functions in the central nervous system, from control of blood flow through to modulation of synaptic activity. Transient increases in intracellular Ca ²⁺ are thought to control these activities. The prevailing concept is that these Ca ²⁺ transients are triggered by distinct pathways, with little mechanistic and functional overlap. Here we demonstrate that astrocytes in visual cortex of mice encode local visual signals in conjunction with arousal state, functioning as multi-modal integrators. Such activity adds an additional layer of complexity to astrocyte function and may enable astrocytes to specifically and subtly regulate local network activity and plasticity.


Sparse orthogonal population representation of spatial context in the retrosplenial cortex

August 2017

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570 Reads

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168 Citations

Sparse orthogonal coding is a key feature of hippocampal neural activity, which is believed to increase episodic memory capacity and to assist in navigation. Some retrosplenial cortex (RSC) neurons convey distributed spatial and navigational signals, but place-field representations such as observed in the hippocampus have not been reported. Combining cellular Ca2+ imaging in RSC of mice with a head-fixed locomotion assay, we identified a population of RSC neurons, located predominantly in superficial layers, whose ensemble activity closely resembles that of hippocampal CA1 place cells during the same task. Like CA1 place cells, these RSC neurons fire in sequences during movement, and show narrowly tuned firing fields that form a sparse, orthogonal code correlated with location. RSC ‘place’ cell activity is robust to environmental manipulations, showing partial remapping similar to that observed in CA1. This population code for spatial context may assist the RSC in its role in memory and/or navigation.



Sparse, Orthogonal Population Representation of Spatial Context in the Retrosplenial Cortex

March 2017

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74 Reads

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10 Citations

General hypothesis: retrosplenial cortex (RSC) mediates hippocampal-neocortical interactions. Question: how RSC neuronal population encodes hippocampus-like sparse, orthogonal position information. Sparse, orthogonal population coding in the hippocampus is believed to maximize episodic memory capacity, minimize memory interference, and assist in navigation. Methods: To study the encoding of positional information in RSC, we used a head-fixed treadmill locomotion assay [1]. Mice were trained to move a treadmill belt for a drop of sucrose water reward delivered at a fixed position on the belt. We performed chronic cellular imaging across RSC subregions with GCaMP6 injections ; we also used Thy1 GP4.3 trans-genic GCaMP6 mice [2-4]. To compare RSC and CA1, we performed chronic cellular imaging in CA1 with a can-nula window [5].


Mesoscale Architecture Shapes Initiation and Richness of Spontaneous Network Activity

March 2017

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480 Reads

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53 Citations

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Spontaneous activity in the absence of external input, including propagating waves of activity, is a robust feature of neuronal networks in vivo and in vitro. The neurophysiological and anatomical requirements for initiation and persistence of such activity, however, are poorly understood, as is their role in the function of neuronal networks. Computational network studies indicate that clustered connectivity may foster the generation, maintenance, and richness of spontaneous activity. Since this mesoscale architecture cannot be systematically modified in intact tissue, testing these predictions is impracticable in vivo. Here, we investigate how the mesoscale structure shapes spontaneous activity in generic networks of rat cortical neurons in vitro. In these networks, neurons spontaneously arrange into local clusters with high neurite density and form fasciculating long-range axons. We modified this structure by modulation of protein kinase C, an enzyme regulating neurite growth and cell migration. Inhibition of protein kinase C reduced neuronal aggregation and fasciculation of axons, i.e., promoted uniform architecture. Conversely, activation of protein kinase C promoted aggregation of neurons into clusters, local connectivity, and bundling of long-range axons. Supporting predictions from theory, clustered networks were more spontaneously active and generated diverse activity patterns. Neurons within clusters received stronger synaptic inputs and displayed increased membrane potential fluctuations. Intensified clustering promoted the initiation of synchronous bursting events but entailed incomplete network recruitment. Moderately clustered networks appear optimal for initiation and propagation of diverse patterns of activity. Our findings support a crucial role of the mesoscale architectures in the regulation of spontaneous activity dynamics.


Cross-modal responses in mouse primary visual cortex during active behavior

October 2015

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33 Reads

Where in our brain do sensory signals first converge to generate multi-modal representations? The dominant view is that it takes place at late processing stages in higher associative cortical areas. Recent studies, however, suggest a role for neurons in early sensory cortices. Most strikingly, this is observed in blind patients in the pronounced activity in visual areas during Braille reading (Sadato et al., 1996). In the rodent visual system, activity is substantially influenced by non-visual signals such as locomotion (Niell and Stryker, 2010; Szuts et al. 2011; Keller et al. 2012), alertness (Reimer et al., 2014), reward (Shuler and Bear, 2006), or cross-modal activity (Wallace et al., 2007). Here, we used a chronic cranial window preparation (Goldey et al., 2014) and cellular imaging to measure network activity in primary visual cortex (V1) of mice engaged in a multimodal exploration task. We trained C57Bl/6 mice to move head-fixed on a virtual linear treadmill track endowed with rich tactile features and a lap-based water reward stop (Royer et al., 2012). We imaged calcium responses of GCaMP6m expressing neurons in V1 layer 2/3 while the animals ran laps on the virtual track. We probed the neurons’ visual responses using brief random visual stimuli presented to the contra-lateral eye as the animals crossed fixed positions on the track. The animals moved intermittently on the track for sessions lasting up to 60 minutes amounting >100 treadmill laps or trials. We related calcium signals to the stimulus, the animal’s movement, and position on the track. We found that V1 neurons show rich, non-visual patterns of activity locked to the animal’s movement and position on the track. Consistent with previous studies (Erisken et al., 2014, Saleem et al., 2013), some neurons show calcium signals that closely reflect locomotion speed while others are activated as animals approach or cross the reward position. Surprisingly, nearly 10% of the neurons also show a position-locked activation that could not be explained by movement or reward. Tightly linked to the presence of tactile cues on the track, this activity occurs in the dark or in lightness, does not require prior exposure to the tactile environment, and is eliminated by blocking whisker access to the cues. These data suggests that congruent tactile inputs and other non-visual signals are readily encoded in V1 population activity. It may be particularly useful for the integration of coinciding and behaviorally relevant signals already at an early processing stage in a primary sensory cortex.


Task-related signals in mouse primary visual cortex during virtual path integration

November 2014

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30 Reads

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1 Citation

Successful navigation and spatial memory requires the integration of multiple information sources into a coherent representation of external sensory features and an animal’s position in space. This convergence is thought to occur in the hippocampal formation, where information about self-motion (path-integration) is used to create a metric representation of space onto which sensory information is superimposed (Navratilova et al., 2012). Recent studies, however, indicate that navigation-related signals are also present at the level of primary sensory areas, possibly reflecting signals from higher processing levels. The functional role of these signals, however, is poorly understood. We studied the encoding of visual and non-visual information in the mouse primary visual cortex (V1) in a ‘virtual’ spatial paradigm comprised of both path-integration and local sensory cues. We developed a head-fixed treadmill assay (Royer et al., 2012) that reliably drives place field activity in the hippocampus and in which visual stimuli can be precisely controlled. We trained mice to move a linear treadmill belt covered with tactile cues and to interrupt their movement at regular intervals for a water reward. We studied how calcium responses of V1 populations to brief visual noise stimuli presented in closed-loop were influenced by task-relevant variables. V1 neurons showed pronounced task-related activity during navigation, even in the absence of visual inputs. Consistent with previous reports, V1 responses to visual stimulation were strongly modulated by movement, with most neurons showing increased responsiveness during motor activity. During visual stimulation, V1 neurons showed reward- and position-related modulations that could not be explained by motor activity and other potentially confounding factors. In the absence of visual inputs, V1 neurons showed signals that reflect distinct aspects of the animal’s behavior, the environment, and the task. These response properties were robust to behavioral variations within imaging sessions and showed even constancy across sessions. We hypothesize that neurons in mouse primary visual cortex encode the conjunction of visual and contextual information, which may be particularly useful in guiding navigational behavior.


Citations (9)


... Another question which so far received less attention is whether sensory modalities other than audition similarly modulate or are represented in V1. Somatosensory and proprioceptive stimuli have been reported to exert modulatory influences on V1 [37,49,[52][53][54], but data are scarcer for other modalities such as taste and smell. As regards gustatory effects, visual responses in higher order visual cortices were reported to be modulated by behaviourally relevant features associated with visual stimuli such as aversive or appetitive taste [55]. ...

Reference:

How ‘visual’ is the visual cortex? The interactions between the visual cortex and other sensory, motivational and motor systems as enabling factors for visual perception
Spatially segregated responses to visuo-tactile stimuli in mouse neocortex during active sensation
  • Citing Preprint
  • September 2019

... In this study, the potentiation of the direction and orientation selectivity of visual cortical neurons to NB stimulation was drastically impaired in conditional inositol-1,4,5 triphosphate receptor-type 2 knockout mice (IP3R2-ko) lacking astrocyte somatic calcium activation. Besides these experiments using strategies to alter neuromodulation, it was also shown that V1 astrocytes in awake mice show calcium responses to visual stimulation (Paukert et al. 2014;Slezak et al. 2019). Nonetheless, this awake activity was also strongly dependent on behavioral state and norepinephrine level, with astrocytes showing stronger activity during locomotion and little activity during stationary resting (Paukert et al. 2014;Slezak et al. 2019). ...

Distinct Mechanisms for Visual and Motor-Related Astrocyte Responses in Mouse Visual Cortex

Current Biology

... They further suggest that astrocyte-based neuromodulation is an ancient feature of the Metazoan nervous system. Moreover, Slezak and colleagues [86] suggested that astrocytes function as multi-modal integrators, encoding visual signals in conjunction with arousal state. Our results support this concept, in which neuromodulators impact network oscillatory activity through parallel activation of both neurons and astrocytes, in which they alter the dynamics of K + clearance to result in transient increase of [K + ] o , thus establishing a synergetic mechanism to maximize their impact on synchronous network activity and recruitment of neurons into networks. ...

Astrocytes integrate local sensory and brain-wide neuromodulatory signals

... Following habituation, animals were trained to run on a linear conveyor belt 150cm in length while head fixed. The conveyor belt has been previously described 70,71 . The conveyor belt was not motorized; all movement of the belt were generated by the mouse. ...

Sparse, Orthogonal Population Representation of Spatial Context in the Retrosplenial Cortex

... Mice learned the task (P < 0.0001 on all mice, Binomial test versus random guessing; Fig. 1c), showing that they learn to form hypotheses about their position during the LM1 phase, retain and update these hypotheses with self-motion information until they encounter the second (perceptually identical) landmark, and use them to disambiguate location and determine the rewarded port. We hypothesized that RSC, which integrates self-motion 5 , position [6][7][8] , reward value 9 and sensory 10 inputs, could perform this computation. RSC is causally required to process landmark information 11 , and we verified that RSC is required for integrating spatial hypotheses with visual information but not for direct visual search with no memory component (Extended Data Fig. 1i-l). ...

Sparse orthogonal population representation of spatial context in the retrosplenial cortex

... Spontaneous network activity underpins the development of functional networks in early stages (Teppola et al., 2019). A hallmark of this activity is the recurrent occurrence of intense, time-constrained network bursts (NBs) that rapidly propagate throughout the entire dissociated culture in vitro (Okujeni et al., 2017;Weihberger et (which was not certified by peer review) is the author/funder. All rights reserved. ...

Mesoscale Architecture Shapes Initiation and Richness of Spontaneous Network Activity

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

... This indicates that the grid firing itself is influenced by sensory cues, thus, even if the place cell firing depended solely on grid cell inputs, it would depend upon both sensory and motor inputs. Not only that, the grid cell firing [63] has also been seen to send inputs to the visual cortex. ...

Task-related signals in mouse primary visual cortex during virtual path integration
  • Citing Poster
  • November 2014

... Little is known how developing networks can reach a final state of self-organized criticality [10,17,21]. In the current paper, we are therefore experimentally investigating the different stages of developing cortical cell cultures [22] to assess under which conditions these networks develop into a critical state. Specifically we are asking the following questions: 1) do the investigated cell cultures undergo a significant transition in their activity states and how is this related to self-organized criticality and 2) can specific predictions be made with respect to network activity and connectivity which would explain the observed behavior. ...

Predicting Spike Activity in Neuronal Cultures

BMC Neuroscience

... Behaviour of animals depends in the main on how brain cells are interconnected (Hohnke & Sur, 2002). Neuro-networks begin with morphological differentiation of neurons followed by increased arborisation, extension of dendrites and increased synaptic density yielding a network of reciprocally interacting units organised for a particular function or functions (Okujeni, Kandler, Weihberger, & Egert, 2009). These 'loops' of neurons are initially imprecise connections that with maturity become increasingly precise (Hohnke & Sur, 2002). ...

Impaired structural plasticity increases connectivity in developing cortical networks

BMC Neuroscience