Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain.

Alzheimer's disease (AD) and dementia in general are age-related diseases with multiple contributing factors, including brain inflammation. Microglia, and specifically those expressing the AD risk gene TREM2, are considered important players in AD, but their exact contribution to pathology remains unclear. In this study, using high-throughput mass cytometry in the 5×FAD mouse model of amyloidosis, we identified senescent microglia that express high levels of TREM2 but also exhibit a distinct signature from TREM2-dependent disease-associated microglia (DAM). This senescent microglial protein signature was found in various mouse models that show cognitive decline, including aging, amyloidosis and tauopathy. TREM2-null mice had fewer microglia with a senescent signature. Treating 5×FAD mice with the senolytic BCL2 family inhibitor ABT-737 reduced senescent microglia, but not the DAM population, and this was accompanied by improved cognition and reduced brain inflammation. Our results suggest a dual and opposite involvement of TREM2 in microglial states, which must be considered when contemplating TREM2 as a therapeutic target in AD.

Time and experience differentially affect distinct aspects of hippocampal representational drift.

Hippocampal activity is critical for spatial memory. Within a fixed, familiar environment, hippocampal codes gradually change over timescales of days to weeks-a phenomenon known as representational drift. The passage of time and the amount of experience are two factors that profoundly affect memory. However, thus far, it has remained unclear to what extent these factors drive hippocampal representational drift. Here, we longitudinally recorded large populations of hippocampal neurons in mice while they repeatedly explored two different familiar environments that they visited at different time intervals over weeks. We found that time and experience differentially affected distinct aspects of representational drift: the passage of time drove changes in neuronal activity rates, whereas experience drove changes in the cells' spatial tuning. Changes in spatial tuning were context specific and largely independent of changes in activity rates. Thus, our results suggest that representational drift is a multi-faceted process governed by distinct neuronal mechanisms.

Organization of hippocampal CA3 into correlated cell assemblies supports a stable spatial code.

Hippocampal subfield CA3 is thought to stably store memories in assemblies of recurrently connected cells functioning as a collective. However, the collective hippocampal coding properties that are unique to CA3 and how such properties facilitate the stability or precision of the neural code remain unclear. Here, we performed large-scale Ca2+ imaging in hippocampal CA1 and CA3 of freely behaving mice that repeatedly explored the same, initially novel environments over weeks. CA3 place cells have more precise and more stable tuning and show a higher statistical dependence with their peers compared with CA1 place cells, uncovering a cell assembly organization in CA3. Surprisingly, although tuning precision and long-term stability are correlated, cells with stronger peer dependence exhibit higher stability but not higher precision. Overall, our results expose the three-way relationship between tuning precision, long-term stability, and peer dependence, suggesting that a cell assembly organization underlies long-term storage of information in the hippocampus.

Representational drift in the mouse visual cortex.

Recent studies have shown that neuronal representations gradually change over time despite no changes in the stimulus, environment, or behavior. However, such representational drift has been assumed to be a property of high-level brain structures, whereas earlier circuits, such as sensory cortices, have been assumed to stably encode information over time. Here, we analyzed large-scale optical and electrophysiological recordings from six visual cortical areas in behaving mice that were repeatedly presented with the same natural movies. Contrary to the prevailing notion, we found representational drift over timescales spanning minutes to days across multiple visual areas, cortical layers, and cell types. Notably, neural-code stability did not reflect the hierarchy of information flow across areas. Although individual neurons showed time-dependent changes in their coding properties, the structure of the relationships between population activity patterns remained stable and stereotypic. Such population-level organization may underlie stable visual perception despite continuous changes in neuronal responses.