Biology subjects

Bonhoeffer, T.

Publications and source records attributed to Bonhoeffer, T..

14 recordsLinked to original sources

bioRxiv2026

Deleting learning-induced dendritic spines disrupts the memory they encode

Long-term memory is widely thought to depend on activity-dependent synaptic plasticity and the structural remodeling that accompanies it, yet direct causal evidence that this remodeling is required for memory storage has been lacking. A case in point is the formation of dendritic spines: new spines appear following learning, but whether they constitute a physical substrate of memory remains unresolved. To address this, we developed the New Spine Elimination Tool (NSET), a chemical-genetic strategy, that ablates dendritic spines formed within a defined window of synaptic plasticity. NSET combines inducible expression of a degradable form of the actin-binding protein Drebrin with ligand-triggered proteasomal degradation. Because mainly nascent spines incorporate the degradable proteins into their cytoskeleton, ligand application eliminates them while sparing pre-existing ones. In hippocampal slice cultures, NSET eliminated recently formed spines without altering overall spine density or affecting pre-existing spines. Applied in vivo in the mouse basolateral amygdala, selective removal of learning-induced spines disrupted auditory fear memory, whereas consolidated memories and the capacity for new learning remained intact. These findings provide direct causal evidence that newly formed dendritic spines are required for long-term memory storage.

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bioRxiv2026

Topography of distance-modulated multisensory object location encoding in mouse area RL

The spatial arrangement of an animals sensory environment is encoded by spatial codes of the external world, often simultaneously in different modalities. How these modalities are brought together in a universal spatial map and how potential differences are reconciled during multisensory integration remains unclear. To tackle this question, we systematically mapped object location receptive fields (OLRFs) across different sensory modalities in area RL, a pivot of visuo-tactile integration within mouse posterior parietal cortex, using a custom high-resolution three-dimensional multisensory stimulation system. Most RL neurons have three-dimensional receptive fields, with many exhibiting OLRFs across visual, tactile (i.e. vibrissal), and bimodal stimulus conditions. Comparing OLRFs across modalities revealed that distance strongly shapes visuo-tactile integration, reflected in the shift of bimodal OLRFs from tactile-dominant to visual-dominant with increasing distance. Distance also affects the linearity and spatial mode of integration. At near distances, neurons integrate object location information sublinearly from overlapping regions of visual and tactile OLRFs. At far distances, information is integrated supralinearly from regions covered by OLRFs of either modality. This distance dependency extends to cortical organization, leading to a distance tuning gradient along which the spatial, modality, and integration properties of RL neurons are aligned. Together, our findings suggest distance as a key factor in visuo-tactile integration, reflecting that the limited reach of whiskers makes visual information more important for farther objects. In parallel, the system shifts from a localization dominated mode for nearby objects to a detection dominated mode for farther objects.

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bioRxiv2023

Sensory experience steers representational drift in mouse visual cortex

Representational drift - the gradual continuous change of neuronal representations - has been observed across many brain areas. It is unclear whether drift is caused by synaptic plasticity elicited by sensory experience, or by the intrinsic volatility of synapses. Here, using chronic two-photon calcium imaging in mouse primary visual cortex, we find that the preferred stimulus orientation of individual neurons slowly drifts over the course of weeks. By using cylinder lens goggles to limit visual experience to a narrow range of orientations, we show that the direction of drift, but not its magnitude, is biased by the statistics of visual input. A network model suggests that drift of preferred orientation largely results from synaptic volatility, which under normal visual conditions is counteracted by experience-driven Hebbian mechanisms, stabilizing preferred orientation. Under deprivation conditions these Hebbian mechanisms enable adaptation. Thus, Hebbian synaptic plasticity steers drift to match the statistics of the environment.

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bioRxiv2023

Ocular dominance columns in mouse visual cortex

The columnar organization of response properties is a fundamental feature of the mammalian visual cortex. However, columns have not been observed universally across all mammalian species. Here, we report the discovery of ocular dominance columns in mouse visual cortex. Our observation in this minute cortical area sets a new boundary condition for models explaining the emergence of columnar organizations in the neocortex.

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bioRxiv2023

DeepD3, an Open Framework for Automated Quantification of Dendritic Spines

Dendritic spines are the seat of most excitatory synapses in the brain, and a cellular structure considered central to learning, memory, and activity-dependent plasticity. The quantification of dendritic spines from light microscopy data is usually performed by humans in a painstaking and error-prone process. We found that human-to-human variability is substantial (inter-rater reliability 82.2{+/-}6.4%), raising concerns about the reproducibility of experiments and the validity of using human-annotated ground truth as an evaluation method for computational approaches of spine identification. To address this, we present DeepD3, an open deep learning-based framework to robustly quantify dendritic spines in microscopy data in a fully automated fashion. DeepD3s neural networks have been trained on data from different sources and experimental conditions, annotated and segmented by multiple experts and they offer precise quantification of dendrites and dendritic spines. Importantly, these networks were validated in a number of datasets on varying acquisition modalities, species, anatomical locations and fluorescent indicators. The entire DeepD3 open framework, including the fully segmented training data, a benchmark that multiple experts have annotated, and the DeepD3 model zoo is fully available, addressing the lack of openly available datasets of dendritic spines while offering a ready-to-use, flexible, transparent, and reproducible spine quantification method.

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bioRxiv2021

Functional and structural features of L2/3 pyramidal cells continuously covary with pial depth in mouse visual cortex

Pyramidal cells of neocortical layer 2/3 (L2/3 PyrCs) integrate signals from numerous brain areas and project throughout the neocortex. Within L2/3, PyrCs show functional and structural specializations depending on their pial depth, indicating participation in different functional microcircuits. However, it is unknown whether these depth-dependent differences result from separable L2/3 PyrC subtypes or whether functional and structural features represent a continuum while correlating with pial depth. Here, we assessed the stimulus selectivity, electrophysiological properties, dendritic morphology, and excitatory and inhibitory synaptic connectivity across the depth of L2/3 in the binocular visual cortex (bV1) of female mice. We find that the structure of the apical but not the basal dendritic tree varies with pial depth, which is accompanied by differences in passive but not active electrophysiological properties. PyrCs in lower L2/3 receive increased excitatory and inhibitory input from L4, while upper L2/3 PyrCs receive a larger proportion of intralaminar input. Complementary in vivo calcium imaging revealed a systematic change in visual responsiveness, with deeper L2/3 PyrCs showing more robust responses than superficial PyrCs. Furthermore, deeper L2/3 PyrCs are more strongly driven by contralateral than ipsilateral eye stimulation. In contrast, orientation- and direction-selectivity of L2/3 PyrCs are not dependent on pial depth. Importantly, the transitions of the various properties are gradual, and cluster analysis does not support the classification of L2/3 PyrCs into discrete subtypes. These results show that L2/3 PyrCs multiple functional and structural properties systematically correlate with their depth within L2/3, forming a continuum rather than representing discrete subtypes. SIGNIFICANCE STATEMENTNeocortical pyramidal cells in layer 2/3 (L2/3 PyrCs) are crucial for cortical computation and display heterogenous properties. We investigated whether and how these properties vary across the depth of L2/3 and whether L2/3 PyrCs can be subdivided into distinct subtypes. This is important for a better understanding of the coding strategy and information integration processes within L2/3. We find that multiple properties such as morphology, physiology, connectivity, and functional in vivo responses of L2/3 PyrCs correlate with cortical depth in mouse visual cortex. These variations are continuous and do not support classification of L2/3 PyrCs into discrete subtypes. In contrast to L5 and L6, PyrCs in L2/3 therefore process information based on a continuous property space.

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bioRxiv2021

Functional network topography of the medial entorhinal cortex

The medial entorhinal cortex (MEC) creates a map of local space, based on the firing patterns of grid, head direction (HD), border, and object-vector (OV) cells. How these cell types are organized anatomically is debated. In-depth analysis of this question requires collection of precise anatomical and activity data across large populations of neurons during unrestrained behavior, which neither electrophysiological nor previous imaging methods fully afford. Here we examined the topographic arrangement of spatially modulated neurons in MEC and adjacent parasubiculum using miniaturized, portable two-photon microscopes, which allow mice to roam freely in open fields. Grid cells exhibited low levels of co-occurrence with OV cells and clustered anatomically, while border, HD and OV cells tended to intermingle. These data suggest that grid-cell networks might be largely distinct from those of border, HD and OV cells and that grid cells exhibit strong coupling among themselves but weaker links to other cell types. Highlights- Grid and object vector cells show low levels of regional co-occurrence - Grid cells exhibit the strongest tendency to cluster among all spatial cell types - Grid cells stay separate from border, head direction and object vector cells - The territories of grid, head direction and border cells remain stable over weeks

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bioRxiv2020

Spaced training enhances memory and prefrontal ensemble stability in mice.

Memory is substantially improved when learning is distributed over time, an effect called "spacing effect". So far it has not been studied how spaced learning affects neuronal ensembles presumably underlying memory. In the present study, we investigate whether trial spacing increases the stability or size of neuronal ensembles. Mice were trained in the "everyday memory" task, an appetitive, naturalistic, delayed matching-to-place task. Spacing trials by 60 minutes produced more robust memories than training with shorter or longer intervals. c-Fos labeling and chemogenetic inactivation established the necessity of the dorsomedial prefrontal cortex (dmPFC) for successful memory storage. In vivo calcium imaging of excitatory dmPFC neurons revealed that longer trial spacing increased the similarity of the population activity pattern on subsequent encoding trials and upon retrieval. Conversely, trial spacing did not affect the size of the total neuronal ensemble or the size of subpopulations dedicated to specific task-related behaviors and events. Thus, spaced learning promotes reactivation of prefrontal neuronal ensembles processing episodic-like memories.

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bioRxiv2020

Selective connectivity limits functional binocularity in the retinogeniculate pathway of the mouse

Eye-specific segregation of retinal ganglion cell (RGC) axons in the dorsal lateral geniculate nucleus (dLGN) is considered a hallmark of visual system development. However, a recent anatomical study showed that nearly half of the neurons in dLGN of adult mice still receive input from both retinae, but functional data about binocularity in mature dLGN is conflicting. Here, we found that a variable but small fraction of thalamocortical neurons is binocular in vivo. Using dual-channel optogenetics in vitro we correspondingly found that dLGN neurons are dominated by retinogeniculate input from one eye only, although most neurons also received small but detectable input from the non-dominant eye. Anatomical overlap between RGC axons and dLGN neuron dendrites did not explain this strong bias towards monocularity. Our data rather suggest that functional input selection and refinement, leaving the remaining non-dominant eye inputs in a juvenile-like state, underlies the prevalent monocularity of neurons in dLGN.

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bioRxiv2020

Relationship between input connectivity, morphology and orientation tuning of layer 2/3 pyramidal cells in mouse visual cortex

Neocortical pyramidal cells (PCs) display functional specializations defined by their excitatory and inhibitory circuit connectivity. For layer 2/3 (L2/3) PCs, little is known about the detailed relationship between their neuronal response properties, dendritic structure and their underlying circuit connectivity at the level of single cells. Here, we ask whether L2/3 PCs in mouse primary visual cortex (V1) differ in their functional intra- and interlaminar connectivity patterns, and how this relates to differences in visual response properties. Using a combined approach, we first characterized the orientation and direction tuning of individual L2/3 PCs with in vivo 2-photon calcium imaging. Subsequently, we performed excitatory and inhibitory synaptic input mapping of the same L2/3 PCs in brain slices using laser scanning photostimulation (LSPS). Our data from this structure-connectivity-function analysis show that the sources of excitatory and inhibitory synaptic input are different in their laminar origin and horizontal location with respect to cell position: On average, L2/3 PCs receive more inhibition than excitation from within L2/3, whereas excitation dominates input from L4 and L5. Horizontally, inhibitory input originates from locations closer to the horizontal position of the soma, while excitatory input arises from more distant locations in L4 and L5. In L2/3, the excitatory and inhibitory inputs spatially overlap on average. Importantly, at the level of individual neurons, PCs receive inputs from presynaptic cells located spatially offset, vertically and horizontally, relative to the soma. These input offsets show a systematic correlation with the preferred orientation of the postsynaptic L2/3 PC in vivo. Unexpectedly, this correlation is higher for inhibitory input offsets within L2/3 than for excitatory input offsets. When relating the dendritic complexity of L2/3 PCs to their orientation tuning, we find that sharply tuned cells have a less complex apical tree compared to broadly tuned cells. These results indicate that the spatial input offsets of the functional input connectivity are linked to orientation preference, while the orientation selectivity of L2/3 PCs is more related to the dendritic complexity.

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bioRxiv2020

Disparity sensitivity and binocular integration in mouse visual cortex areas

Binocular disparity, the difference between the two eyes images, is a powerful cue to generate the three-dimensional depth percept known as stereopsis. In primates, binocular disparity is processed in multiple areas of the visual cortex, with distinct contributions of higher areas to specific aspects of depth perception. Mice, too, can perceive stereoscopic depth, and neurons in primary visual cortex (V1) and higher-order, lateromedial (LM) and rostrolateral (RL) areas were found to be sensitive to binocular disparity. A detailed characterization of disparity tuning properties across mouse visual areas is lacking, however, and acquiring such data might help clarifying the role of higher areas for disparity processing and establishing putative functional correspondences to primate areas. We used two-photon calcium imaging to characterize the disparity tuning properties of neurons in mouse visual areas V1, LM, and RL in response to dichoptically presented binocular gratings, as well as correlated and anticorrelated random dot stereograms (RDS). In all three areas, many neurons were tuned to disparity, showing strong response facilitation or suppression at optimal or null disparity, respectively. This was even the case in neurons classified as monocular by conventional ocular dominance measurements. Spatial clustering of similarly tuned neurons was observed at a scale of about 10 m. Finally, we probed neurons sensitivity to true stereo correspondence by comparing responses to correlated and anticorrelated RDS. Area LM, akin to primate ventral visual stream areas, showed higher selectivity for correlated stimuli and reduced anticorrelated responses, indicating higher-level disparity processing in LM compared to V1 and RL.

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bioRxiv2019

Area-specific mapping of binocular disparity across mouse visual cortex

Binocular disparity, the difference between left and right eye images, is a powerful cue for depth perception. Many neurons in the visual cortex of higher mammals are sensitive to binocular disparity, with distinct disparity tuning properties across primary and higher visual areas. Mouse primary visual cortex (V1) has been shown to contain disparity-tuned neurons, but it is unknown how these signals are processed beyond V1. We find that disparity signals are prominent in higher areas of mouse visual cortex. Preferred disparities markedly differ among visual areas, with area RL encoding visual stimuli very close to the mouse. Moreover, disparity preference is systematically related to visual field elevation, such that neurons with receptive fields in the lower visual field are overall tuned to near disparities, likely reflecting an adaptation to natural image statistics. Our results reveal ecologically relevant areal specializations for binocular disparity processing across mouse visual cortex.

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bioRxiv2018

Benchmarking miniaturized microscopy against two-photon calcium imaging using single-cell orientation tuning in mouse visual cortex

Miniaturized microscopes are lightweight imaging devices that allow optical recordings from neurons in freely moving animals over the course of weeks. Despite their ubiquitous use, individual neuronal responses measured with these microscopes have not been directly compared to those obtained with established in vivo imaging techniques such as bench-top two-photon microscopes. To achieve this, we performed calcium imaging in mouse primary visual cortex while presenting animals with drifting gratings. We identified the same neurons in image stacks acquired with both microscopy methods and quantified orientation tuning of individual neurons. The response amplitude and signal-to-noise ratio of calcium transients recorded upon visual stimulation were highly correlated between both microscopy methods, although influenced by neuropil contamination in miniaturized microscopy. Tuning properties, calculated for individual orientation tuned neurons, were strongly correlated between imaging techniques. Thus, neuronal tuning features measured with a miniaturized microscope are quantitatively similar to those obtained with a two-photon microscope.

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bioRxiv2017

Lateral geniculate neurons show robust ocular dominance plasticity

Experience-dependent plasticity in the mature visual system is considered exclusively cortical. Using chronic two-photon Ca2+ imaging, we found evidence against this tenet: dLGN cells showed robust ocular dominance shifts after monocular deprivation. Most, but not all responses of dLGN cell boutons in binocular visual cortex were monocular during baseline. Following deprivation, however, deprived-eye dominated boutons became responsive to the non-deprived eye. Thus, plasticity of dLGN neurons contributes to cortical ocular dominance shifts.

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