Highlights d The visual cortex exhibits representational drift over minutes to days d Drift is characterized by both changes in cells' activity rates and tuning d Neural-code stability does not follow the hierarchy of the visual system d The relationships between population activity patterns remain stable over time

Neuronal representations in the hippocampus and related structures gradually change over time despite no changes in the environment or behavior. The extent to which such ‘representational drift’ occurs in sensory cortical areas and whether the hierarchy of information flow across areas affects neural-code stability have remained elusive. Here, we address these questions by analyzing large-scale optical and electrophysiological recordings from six visual cortical areas in behaving mice that were repeatedly presented with the same natural movies. We found representational drift over timescales spanning minutes to days across multiple visual areas. The drift was driven mostly by changes in individual cells’ activity rates, while their tuning changed to a lesser extent. Despite these changes, the structure of relationships between the population activity patterns remained stable and stereotypic, allowing robust maintenance of information over time. Such population-level organization may underlie stable visual perception in the face of continuous changes in neuronal responses.

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Dementia in general, and Alzheimer's disease (AD) in particular, are age-related diseases (1,2). AD is associated with multiple causative factors (3,4), among which local brain inflammation plays a significant role (5). Microglia, the brain-resident immune cells, are activated along the disease course (6,7). Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor (8,9). A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-73710,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach.