Biology subjects

Wenderski, W.

Publications and source records attributed to Wenderski, W..

4 recordsLinked to original sources

bioRxiv2026

Intrinsic space-time couplings governing multi-scale cortical dynamics

The neocortex covers a vast expanse of the mammalian brain and represents the principal target of clinical neuromodulation; however, the global principles of neocortical operation have been challenging to identify. In this regard, a limitation has been tracking activity with cortex-wide spatial coverage while maintaining access to the millisecond temporal resolution of neuronal firing-- a crucial combination not achievable with existing recording technologies. Here we introduce and apply conformal immersion microscopy, enabling activity tracking across the entire dorsal cortex with millisecond temporal resolution and 100 {micro}m spatial resolution (thus spanning five orders of magnitude in time and four in space), at sufficient sensitivity to resolve single-trial activity beyond 100 Hz. Drawing on physics-based frameworks, we apply multiscale analysis to identify a fundamental frequency-dependent coherence length that partitions the neocortex into discrete dynamical elements with well-defined propagation speeds, boundaries, and scale-invariant dynamics. These dynamical elements were found to be conserved from sub-threshold to suprathreshold (neuronal firing) regimes of neural activity, and were robust to diverse pharmacological, optogenetic, and genetic interventions. However, it was possible to identify and establish conditions allowing elemental boundaries to be selectively overridden, and to allow perturbation of specific elements even while conserving global dynamical architecture. Together, these findings enable measurement of intrinsic spatiotemporal parameters governing the dynamical organization of neocortex, which may provide a foundation for mechanistically-informed basic and translational understanding.

neuroscience↗

bioRxiv2026

Causal and directional elements of global brain dynamics

Mammalian cognition appears to involve coordinated neural activity within and across brain-spanning networks. However, the governing principles of large-scale integration remain largely unknown. Here we developed an approach to record spontaneous cortex-wide neural activity (including with novel genetically encoded activity sensors), over very long timescales, and applied unbiased computation to capture conserved spatiotemporal regularities in these data. Initial screening extracted a set of directional elements: consistent spatiotemporal patterns of cortical activity that generalized across excitatory and inhibitory neuronal cell types as revealed by genetic targeting of activity sensors. In particular, novel genetically encoded voltage-sensing strategies revealed that the directional elements were not only highly conserved, but also were represented across the full neural activity frequency spectrum including the fastest timescales (gamma rhythms) enabled by voltage-sensing. Exploiting the spatiotemporal structure revealed by these directional elements, we tested for causal rules governing cortical network activation, using patterned optogenetic stimulation combined with activity imaging. We found that the directional propagation structure of these elements encoded a causal control hierarchy, as source regions (but not sink regions) sufficed to drive full element recruitment--a principle that held across all tested directional elements. Employing a panel of psychotropic drugs, we showed that directional element structure and excitability were robust to manipulations of neural and behavioral state, even as spontaneous network dynamics were reshaped in compound-specific ways. Finally, we developed and applied an all-optical sensing/control approach targeting the directional elements in a behavioral visual detection paradigm, revealing contributions of these conserved large-scale dynamics to elevated sensorimotor behavioral performance.

neuroscience↗

bioRxiv2023

Synaptic Activity Causes Minute-scale Changes in BAF Complex Composition and Function

Genes encoding subunits of the SWI/SNF or BAF ATP-dependent chromatin remodeling complex are among the most enriched for deleterious de novo mutations in intellectual disabilities and autism spectrum disorder, but the causative molecular pathways are not fully known1,2. Synaptic activity in neurons is critical for learning and memory and proper neural development3. Neural activity prompts calcium influx and transcription within minutes, facilitated in the nucleus by various transcription factors (TFs) and chromatin modifiers4. While BAF is required for activity-dependent developmental processes such as dendritic outgrowth5-7, the immediate molecular consequences of neural activity on BAF complexes and their functions are unknown. Here we mapped minute-scale biochemical consequences of neural activity, modeled by membrane depolarization of embryonic mouse primary cortical neurons, on BAF complexes. We used acute chemical perturbations of BAF ATPase activity and kinase signaling to define the activity-dependent effects on BAF complexes and activity-dependent BAF functions. Our studies found that BAF complexes change in subunit composition and are selectively phosphorylated within 10 minutes of depolarization. Increased levels of the core PBAF subunit Baf200/Arid2, uniquely containing an RFX-like DNA-binding domain, are concurrent with ATPase-dependent opening of chromatin at RFX/X-box motifs. Changes in BAF composition and phosphorylation lead to the regulation of chromatin accessibility for critical neurogenesis TFs. These biochemical effects are a convergent phenomenon downstream of multiple growth factor signaling pathways in mouse neurons and fibroblasts suggesting that BAF integrates signaling information from the membrane. In support of such a membrane-to-nucleus signaling cascade, we also identified a BAF-interacting kinase, Dclk2, whose inhibition attenuates BAF phosphorylation selectively. Our findings support a direct role of BAF complexes in responding to synaptic activity to regulate TF binding and transcription.

molecular biology↗

bioRxiv2022

Rewiring Cancer Drivers to Activate Apoptosis

Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1-6. Independent studies have identified cell death pathways that eliminate cells for the good of the organism7-10. The coexistence of the cell death pathways with the driver mutations suggest that the cancer driver could be rewired to activate cell death. We have invented a new class of molecules: TCIPs (Transcriptional/Epigenetic Chemical Inducers of Proximity) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes thereby activating their expression. To develop this concept, we have focused on diffuse large B cell lymphoma (DLBCL), in which BCL6 is amplified or mutated11. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression12. We produced the first TCIPs by chemically linking BCL6 inhibitors to small molecules that bind transcriptional activators. Several of these molecules robustly kill DLBCL at single-digit nanomolar concentrations, including chemotherapy-resistant, TP53-mutant lines. The dominant gain-of-function approach provided by TCIPs captures the combinatorial specificity inherit to transcription and can thereby accesses new therapeutic space. TCIPs are relatively non-toxic to normal cells and mice, apparently reflecting their need for coincident expression of both target proteins for effective killing. The general TCIP concept has applications in elimination of senescent cells, enhancing expression of therapeutic genes, treatment of diseases produced by haploinsufficiency, and activation of immunogens for immunotherapy.

cancer biology↗