Biology subjects

Siverts, L.

Publications and source records attributed to Siverts, L..

6 recordsLinked to original sources

bioRxiv2026

Raster photostimulation of large-scale neural populations

Neural computations are implemented by distributed neural populations that typically span multiple brain areas. Simultaneous recording and photo-activation experiments can reveal the structure and logic of these neural computations, but such methods are typically limited to small subsets of neurons in restricted fields of view. Here we describe a new system called raster photostimulation for activating and recording thousands of neurons, over a short 300 ms time window and over a large 5 mm field-of-view on a two-photon mesoscope. The photo-activation is precisely matched to the neural recording configuration, as it uses the same optical path, although with a different laser that is independently gated. We demonstrate pixel-level precision, frame-by-frame mask updating, and single-frame photostimulation of thousands of neurons. While this method lacks the precise temporal control of alternative methods, it compensates with ease-of-use, spatial precision, cost of implementation and by pushing the limits on the number of near-simultaneously stimulated neurons.

neuroscience↗

bioRxiv2025

Environmental Novelty Modulates Rapid Cortical Plasticity During Navigation

In novel environments, animals quickly learn to navigate, and position-correlated spatial representations rapidly emerge in both the retrosplenial cortex (RSC) and primary visual cortex (V1). However, the role of plasticity in building these spatial representations, and how experience modulates this process, are not well understood. Here, we investigated the plasticity of spatial representations with real-time, cellular-resolution read and write control of neural activity using two-photon calcium imaging combined with holographic optogenetic stimulation in mice navigating virtual reality environments. Targeted stimulation of individual layer 2/3 neurons rapidly biased neural activity towards stimulation-paired locations in novel, but not familiar, environments. In contrast, RSC layer 5 neurons exhibited stimulation-induced plasticity regardless of environmental familiarity. These findings reveal a layer-specific, experience-dependent modulation of plasticity and offer a framework for how neocortical spatial representations strike a balance between stability of familiar environments with flexibility for continuous updates of relevant context information. HighlightsO_LIAll optical read-write approach reveals experience-dependent plasticity in cortex C_LIO_LIStimulating layer 2/3 neurons biases activity in novel but not familiar environments C_LIO_LILayer 5 neurons exhibit plasticity regardless of environmental familiarity C_LI

neuroscience↗

bioRxiv2025

Large-scale cellular-resolution read/write of activity enables discovery of cell types defined by complex circuit properties

The complexity of the mammalian brains vast population of interconnected neurons poses a formidable challenge to elucidate its underlying mechanisms of coordination and computation. A key step forward will be technologies that can perform large-scale, cellular-resolution monitoring and interrogation of distributed brain circuit activity in behaving animals. Here, we present an all-optical strategy for precise optogenetic activity control of [~]103 neurons and simultaneous activity monitoring of [~]104 neurons within and across areas of mouse cortex--an order-of-magnitude leap beyond previous capabilities. Tracking population responses following delivery of precisely-defined widely-distributed activity patterns to the visual cortex of awake mice, we were surprised to identify neurons robustly responsive to stimulation of diverse ensembles, defying conventional like-to-like wiring rules. These cells were primarily deep L2/3 somatostatin-positive (SST) interneurons with functional properties distinct from other SST neurons, and appeared to play a role in brain dynamics that could only have been identified through broad cellular-resolution circuit interrogation. Our work reveals the value of measuring large-scale circuit-dynamical properties of functionally-resolved single cells, beyond genetic and anatomical classification, to define and explore the roles of cell types in brain function.

neuroscience↗

bioRxiv2024

Cholinergic Neuronal Activity Promotes Diffuse Midline Glioma Growth through Muscarinic Signaling

Neuronal activity promotes the proliferation of healthy oligodendrocyte precursor cells (OPC) and their malignant counterparts, gliomas. Many gliomas arise from and closely resemble oligodendroglial lineage precursors, including diffuse midline glioma (DMG), a cancer affecting midline structures such as the thalamus, brainstem and spinal cord. In DMG, glutamatergic and GABAergic neuronal activity promotes progression through both paracrine signaling and through bona-fide neuron-to-glioma synapses. However, the putative roles of other neuronal subpopulations - especially neuromodulatory neurons located in the brainstem that project to long-range target sites in midline anatomical locations where DMGs arise - remain largely unexplored. Here, we demonstrate that the activity of cholinergic midbrain neurons modulates both healthy OPC and malignant DMG proliferation in a circuit-specific manner at sites of long-range cholinergic projections. Optogenetic stimulation of the cholinergic pedunculopontine nucleus (PPN) promotes glioma growth in pons, while stimulation of the laterodorsal tegmentum nucleus (LDT) facilitates proliferation in thalamus, consistent with the predominant projection patterns of each cholinergic midbrain nucleus. Reciprocal signaling was evident, as increased activity of cholinergic neurons in the PPN and LDT was observed in pontine DMG-bearing mice. In co-culture, hiPSC-derived cholinergic neurons form neuron-to-glioma networks with DMG cells and robustly promote proliferation. Single-cell RNA sequencing analyses revealed prominent expression of the muscarinic receptor genes CHRM1 and CHRM3 in primary patient DMG samples, particularly enriched in the OPC-like tumor subpopulation. Acetylcholine, the neurotransmitter cholinergic neurons release, exerts a direct effect on DMG tumor cells, promoting increased proliferation and invasion through muscarinic receptors. Pharmacological blockade of M1 and M3 acetylcholine receptors abolished the activity-regulated increase in DMG proliferation in cholinergic neuron-glioma co-culture and in vivo. Taken together, these findings demonstrate that midbrain cholinergic neuron long-range projections to midline structures promote activity-dependent DMG growth through M1 and M3 cholinergic receptors, mirroring a parallel proliferative effect on healthy OPCs. HIGHLIGHTSO_LIActivity of midbrain cholinergic neuron long-range projections increases proliferation of both healthy oligodendrocyte precursor cells (OPC) and malignant diffuse midline glioma (DMG) cells. C_LIO_LIOptogenetic stimulation of cholinergic midbrain nuclei promotes growth in thalamic and pontine glioma in a circuit-dependent manner. C_LIO_LIReciprocally, DMG cells increase cholinergic neuronal activity in cholinergic midbrain nuclei. C_LIO_LIThe muscarinic receptors CHRM1 and CHRM3 are identified as therapeutic targets in DMG. C_LI

neuroscience↗

bioRxiv2021

Connectivity and Synaptic Physiology in the Mouse and Human Cortex

To elucidate cortical microcircuit structure and synaptic properties we present a unique, extensive, and public synaptic physiology dataset and analysis platform. Through its application, we reveal principles that relate cell type to synapse properties and intralaminar circuit organization in the mouse and human cortex. The dynamics of excitatory synapses align with the postsynaptic cell subclass, whereas inhibitory synapse dynamics partly align with presynaptic cell subclass but with considerable overlap. Despite these associations, synaptic properties are heterogeneous in most subclass to subclass connections. The two main axes of heterogeneity are strength and variability. Cell subclasses divide along the variability axis, while the strength axis accounts for significant heterogeneity within the subclass. In human cortex, excitatory to excitatory synapse dynamics are distinct from those in mouse and short-term plasticity varies with depth across layers 2 and 3. With a novel connectivity analysis that enables fair comparisons between circuit elements, we find that intralaminar connection probability among cell subclasses exhibits a strong layer dependence.These and other findings combined with the analysis platform create new opportunities for the neuroscience community to advance our understanding of cortical microcircuits.

neuroscience↗

bioRxiv2017

A suite of transgenic driver and reporter mouse lines with enhanced brain cell type targeting and functionality

Modern genetic approaches are powerful in providing access to diverse types of neurons within the mammalian brain and greatly facilitating the study of their function. We here report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically-defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.

neuroscience↗