Biology subjects

Willig, K. I.

Publications and source records attributed to Willig, K. I..

6 recordsLinked to original sources

bioRxiv2026

Signatures of Hebbian plasticity in the nanoscale morphodynamics of cortical spines

The size, shape, and nanoscale organization of synaptic spines are predictive of physiological synaptic strength and thus key to connectome-based neural circuit models. In the intact brain, spine size and shape undergo continuous morphological remodeling. While these nanoscale morphodynamics are not well understood, it is clear that morphological changes that strongly impact synaptic strength should modify spine head and neck in a coordinated manner and that such coordinated remodeling can be triggered by spike-timing-dependent synaptic plasticity. Here we demonstrate unambiguous signatures of such coordinated spine remodeling from in vivo long-term nanoscopy of cortical spines. We infer data-driven generative models of synaptic spine morphodynamics. These models imply that although coordinated remodeling represents the smallest component of ongoing morphodynamic fluctuations, this component causes massive fluctuations in instantaneous synaptic strength. Despite these fluctuations, synaptic strengths exhibit a synapse-specific long-term persistent component that results from spine fluctuations exploring only a limited subregion of accessible spine morphospace. Our results suggest that nanoscale morphodynamic spine remodeling injects substantial fluctuations of instantaneous synaptic strength into the operation of cortical circuits. Connectome-based neural circuit models thus need to consider features of spine organization beyond spine head size and should be augmented by data-driven generative models of spine morphodynamics.

neuroscience↗

bioRxiv2023

Pre- and postsynaptic nanostructures increase in size and complexity after LTP induction

Synapses, specialized contact sites between neurons, are the fundamental elements of neuronal information transfer. Synaptic plasticity is related to changes in synaptic morphology and the number of neurotransmitter receptors, and thought to underlie learning and memory. However, it is not clear how these structural and functional changes are connected. We utilized time-lapse super-resolution STED microscopy to visualize structural changes of the synaptic nano-organization of the postsynaptic scaffolding protein PSD95, the presynaptic scaffolding protein Bassoon, and the GluA2 subunit of AMPA receptors by chemically induced long-term potentiation (cLTP) at the level of single synapses. We found that the nano-organization of all three proteins undergoes an increase in complexity and size after cLTP induction. The increase was largely synchronous, peaking at [~]60 min after stimulation. Therefore, both the size and complexity of single pre- and post-synaptic nanostructures serve as substrates for adjusting and determining synaptic strength. Highlights- Time-lapse super-resolution images the structural changes of the PSD95 nano-organization after Cltp - cLTP-induced growth of the PSD95 nano-organization is less than spine head growth and peaks at 60 min, i.e. much slower than the increase in spine volume. - Most PSD95 nanostructures increase in complexity upon cLTP. - Synchronous growth - Nanostructures of pre- and postsynaptic scaffolding proteins and AMPA receptors increase simultaneously and equally strong upon cLTP. - GluA2-containing synaptic AMPA receptors form nanoclusters that increase in size and slightly in number upon cLTP and form subdomains on PSD95. - Bassoon forms complex structures similar to the PSD95 nano-organization.

neuroscience↗

bioRxiv2022

Perineuronal net loosening associates with the remodeling of GABAergic terminals on motor cortical layer 5 interneurons and precedes motor coordination recovery post stroke

Stroke remains one of the leading causes of long-term disability worldwide, and the development of effective restorative therapies is hindered by an incomplete understanding of intrinsic brain recovery mechanisms. Here we explored how perineuronal nets (PNNs), the facet-like extracellular matrix layers surrounding fast-spiking interneurons, contribute to neurological recovery after focal cerebral ischemia in mice with and without induced stroke tolerance. Due to the insufficient resolution of conventional microscopy methods, the contribution of structural changes in PNNs to post stroke brain plasticity remained unknown. Using superresolution stimulated emission depletion (STED) and structured illumination (SR-SIM) microscopy, we revealed that PNN facets become larger and less dense in the post-acute stroke phase. These morphological alterations in PNNs are transient and correlate with the increased surface of contact between activated microglia and PNN-coated neurons. The transient loosening of PNNs after stroke allows for dynamic reorganization of GABAergic axonal terminals on inhibitory interneurons in the motor cortical layer 5. The coherent remodeling of PNNs and their perforating inhibitory synapses precedes the recovery of motor coordination after stroke and depends on the severity of the ischemic injury. Our data suggest a novel mechanism of motor cortical plasticity after stroke, and we propose that prolonging PNN loosening during the post-acute period can extend the opening neuroplasticity window into the chronic stroke phase. HighlightsO_LIPNNs are degraded partially and transiently post-stroke C_LIO_LITransient attenuation of PNNs correlates with GABAergic synapse remodeling C_LIO_LITransient attenuation of PNNs precedes functional recovery post stroke C_LIO_LIActivated microglia preferentially contact PNN-coated neurons post stroke C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/510951v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@13815d3org.highwire.dtl.DTLVardef@1210182org.highwire.dtl.DTLVardef@1ea12e6org.highwire.dtl.DTLVardef@7ed5b1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Environmental enrichment enhances precision and remodeling speed of synaptic nanoarchitecture revealed by crosstalk free two-color in vivo STED nanoscopy

Synaptic plasticity underlies long-lasting structural and functional changes to brain circuitry and its experience-dependent remodeling can be fundamentally enhanced by environmental enrichment. It is unknown, however, whether and how environmental enrichment alters the morphology and dynamics of individual synapses. Here, we present a virtually crosstalk free, two-color in vivo STED microscope to simultaneously superresolve the dynamics of endogenous PSD95 of the post-synaptic density and spine geometry. With environmental enrichment, the size distributions of PSD95 and spine head sizes were sharper than in controls, indicating that synaptic strength is set more precisely with environmental enrichment. Spine head geometry and PSD95 assemblies were highly dynamic but their changes correlated only mildly. With environmental enrichment, the topography of the PSD95 nanoorganization was more dynamic; changes in size were smaller than in mice housed in standard cages and depended linearly on their original size. Thus, two-color in vivo time-lapse imaging of synaptic nanoorganization uncovers a unique synaptic nanoplasticity associated with the enhanced learning capabilities under environmental enrichment.

neuroscience↗

bioRxiv2020

Chronic in vivo STED nanoscopy uncovers multiple drivers of shape volatility in stable cortical spines

Excitatory synapses on dendritic spines of pyramidal neurons are considered a central memory locus. To foster both continuous adaption as well as the storage of long-term information, spines need to be plastic and stable at the same time. Here we advanced in vivo STED nanoscopy to superresolve distinct features of dendritic spines (head size, neck length and width) in mouse neocortex for up to one month. While LTP-dependent changes predict highly correlated modifications of spine geometry, we find both, uncorrelated dynamics, as well as correlated changes, indicating multiple independent drivers of spine remodeling. The magnitude of this remodeling suggests substantial fluctuations in synaptic strength, and is exaggerated in a mouse model of neurodegeneration. Despite this high degree of volatility, all spine features also exhibit persistent components that are maintained over long periods of time. Thus, at the nanoscale, stable dendritic spines exhibit a delicate balance of stability and volatility.

neuroscience↗

bioRxiv2018

A Proof-of-Principle of Nanoscale Optogenetics

Optogenetics has revolutionized the study of circuit function in the brain, by allowing activation of specific ensembles of neurons by light. However, this technique has not yet been exploited extensively at the subcellular level. Here we propose a novel focal stimulation approach using STED/RESOLFT-like illumination, whereby switchable light-gated channels are focally activated by a laser beam of one wavelength and deactivated by an overlapping donut-shaped beam of a different wavelength, confining activation to a center focal region. We demonstrate the utility of current optogenetic tools to achieve highly focal depolarization using this method and further examine a proof-of-principle of nanoscale optogenetic activation using an initial macroscale approach. When employed at the nanoscale, this approach will allow unprecedented optogenetic control of nanodomains within cells.

neuroscience↗