Highlights d Auditory gamma entrainment using sensory stimuli (GENUS) boosts hippocampal function d GENUS affects microglia, astrocytes, and vasculature in auditory cortex and hippocampus d Auditory plus visual GENUS induces microglia clustering around plaques d Auditory plus visual GENUS reduces amyloid pathology throughout neocortex

Highlights d 5XFAD mice have weakened inhibitory synaptic efficacy during behavior d Weakened inhibition in 5XFAD mice occurs during sharpwave ripples d 5XFAD mice have fewer and shorter sharp-wave ripples d Place cell reactivation is impaired during the remaining ripples in 5XFAD mice

Magnetic iron oxide nanoparticles (MNPs) have been developed for magnetic fluid hyperthermia (MFH) cancer therapy, where cancer cells are treated through the heat generated by application of a high frequency magnetic field. This heat has also been proposed as a mechanism to trigger release of chemotherapy agents. In each of these cases, MNPs with optimal heating performance can be used to maximize therapeutic effect while minimizing the required dosage of MNPs. In this study, the heating efficiencies (or specific absorption rate, SAR) of two types of MNPs were evaluated experimentally and then predicted from their magnetic properties. MNPs were also incorporated in the core of poly(ethylene glycol-b-caprolactone) micelles, co-localized with rhodamine B fluorescent dye attached to polycaprolactone to monitor local, nanoscale temperatures during magnetic heating. Despite a relatively high SAR produced by these MNPs, no significant temperature rise beyond that observed in the bulk solution was measured by fluorescence in the core of the magnetic micelles. MNPs were also incorporated into a macro-scale agarose gel system that mimicked a tumor targeted by MNPs and surrounded by healthy tissues. The agarose-based tumor models showed that targeted MNPs can reach hyperthermia temperatures inside a tumor with a sufficient MNP concentration, while causing minimal temperature rise in the healthy tissue surrounding the tumor.

Significance Goal-directed spatial navigation has been found to rely on hippocampal neurons that are spatially modulated. We show that “nonplace” cells without significant spatial modulation play a role in discriminating goals when environmental cues for goals are ambiguous. This nonplace cell activity is performance-dependent and is modulated by gamma oscillations. Finally, nonplace cell goal discrimination coding fails in a mouse model of Alzheimer’s disease (AD). Together, these results show that nonplace cell firing can signal unique task-relevant information when spatial information is ambiguous; these signals depend on performance and are absent in a mouse model of AD.

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Rhythmic neural activity, which coordinates brain regions and neurons to achieve multiple brain functions, is impaired in many diseases. Despite the therapeutic potential of driving brain rhythms, methods to noninvasively target deep brain regions are limited. Accordingly, we recently introduced a noninvasive stimulation approach using flickering lights and sounds (“flicker”). Flicker drives rhythmic activity in deep and superficial brain regions. Gamma flicker spurs immune function, clears pathogens, and rescues memory performance in mice with amyloid pathology. Here we present substantial improvements to this approach that is flexible, user-friendly, and generalizable across multiple experimental settings and species. We present novel open-source methods for flicker stimulation across rodents and humans. We demonstrate rapid, cross-species induction of rhythmic activity without behavioral confounds in multiple settings from electrophysiology to neuroimaging. This flicker approach provides an exceptional opportunity to discover the therapeutic effects of brain rhythms across scales and species.Significance StatementDespite many studies showing abnormal brain rhythms in multiple diseases, limited means to target deep brain regions noninvasively has restricted the therapeutic potential of driving brain rhythms. Accordingly, we developed a noninvasive millisecond precise sensory stimulation to drive brain rhythms. Here we introduce for the first time newly developed open-source software and instructions for building, testing, debugging, and using BrainWAVE (Brain Wide-spectrum Audio/Visual Exposure) stimulation. We demonstrate BrainWAVE stimulation across multiple species and different experimental settings. These methods constitute a customizable, open-source, accessible, and non-invasive technology that stimulates brain oscillations to causally test how rhythmic brain activity impacts brain function.