SUMMARY Neuronal activity causes the rapid expression of immediate early genes that are crucial for experience-driven changes to synapses, learning, and memory. Here, using both molecular and genome-wide next-generation sequencing methods, we report that neuronal activity stimulation triggers the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including Fos, Npas4, and Egr1. Generation of targeted DNA DSBs within Fos and Npas4 promoters is sufficient to induce their expression even in the absence of an external stimulus. Activity-dependent DSB formation is likely mediated by the type II topoisomerase, Topoisomerase IIβ (Topo IIβ), and knockdown of Topo IIβ attenuates both DSB formation and early-response gene expression following neuronal stimulation. Our results suggest that DSB formation is a physiological event that rapidly resolves topological constraints to early-response gene expression in neurons.

Neuronal and synaptic loss is characteristic in many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer's disease. Recently, we showed that inducing gamma oscillations with visual stimulation (gamma entrainment using sensory stimuli, or GENUS) reduced amyloid plaques and phosphorylated tau in multiple mouse models. Whether GENUS can affect neurodegeneration or cognitive performance remains unknown. Here, we demonstrate that GENUS can entrain gamma oscillations in the visual cortex, hippocampus, and prefrontal cortex in Tau P301S and CK-p25 mouse models of neurodegeneration. Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early stages of neurodegeneration showed a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance. Our transcriptomic and phosphoproteomic data suggest that chronic GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective factors, and reducing DNA damage in neurons while also reducing inflammatory response in microglia.(D) Representative spectra of LFPs recorded simultaneously from V1, SS1, CA1, and PFC. (E) Normalized group gamma power (see Figure S1C). n = 7 mice. Wilcoxon-Rank sum test; V1, Z = 5.9, p < 0.0001; SS1, Z = 2.4, p = 0.018; CA1, Z = 3.4, p < 0.0001; and PFC, Z = 3.3, p < 0.0001. (F) Raster plots of single CA1 units (labeled in different colors) with concurrently recorded LFP (band-pass filtered for 30-50 Hz) from two representative mice. (G) Spike probability of all isolated CA1 units across 40-Hz phase. (H) Phase locking strength of neuronal spikes to local LFP analyzed by mean resultant length (n = 24 cells from 4 mice. Wilcoxon-Rank sum, Z = 2.5, p = 0.011). Mean firing rate of single CA1 units did not differ between occluded (2.0 ± 0.12 Hz) and visible 40-Hz stimulation (2.1 ± 0.13 Hz) (Z = 0.55, p = 0.58). (I) LFP coherence between pairs of recording sites, as indicated, quantified using WPLI (n = 7 mice; 40-Hz visual stimulation occluded [blue] and visible [red]). (J) Group changes in low gamma band (30-50 Hz) WPLI, related to (I)

SUMMARY We present a consensus atlas of the human brain transcriptome in Alzheimer’s disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington’s disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.