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Introduction: The study of the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular -amyloid (A) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. Methods: The humanized APPNL-G-F knock-in mouse line was crossed to the PS19 MAPTP301S, over-expression mouse line to create the dual APPNL-G-F/PS19 MAPTP301S line. The resulting pathologies were characterized by immunochemical methods and PCR. Results: We now report on a double transgenic APPNL-G-F/PS19 MAPTP301S mouse that at 6 months of age exhibits robust A plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of A pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. MAPT pathology neither changed levels of amyloid precursor protein nor potentiated A accumulation. Interestingly, study of immunofluorescence in cleared brains indicates that microglial inflammation was generally stronger in the hippocampus, dentate gyrus and entorhinal cortex, which are regions with predominant MAPT pathology. The APPNL-G-F/MAPTP301S mouse model also showed strong accumulation of N6-methyladenosine (m6A), which was recently shown to be elevated in the AD brain. m6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively. Discussion: Our understanding of the pathophysiology of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular -amyloid (A) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. The APPNL-G-F/MAPTP301S mouse recapitulates many features of AD pathology beginning at 6 months of aging, and thus represents a useful new mouse model for the field.
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Mouse pups produce. ultrasonic vocalizations (USVs) in response to isolation from the nest (i.e., isolation USVs). Rates and acoustic features of isolation USVs change dramatically over the first two weeks of life, and there is also substantial variability in the rates and acoustic features of isolation USVs at a given postnatal age. The factors that contribute to within age variability in isolation USVs remain largely unknown. Here, we explore the extent to which non-vocal behaviors of mouse pups relate to the within age variability in rates and acoustic features of their USVs. We recorded non-vocal behaviors of isolated C57BL/6J mouse pups at four postnatal ages (postnatal days 5, 10, 15, and 20), measured rates of isolation USV production, and applied a combination of pre-defined acoustic feature measurements and an unsupervised machine learning-based vocal analysis method to examine USV acoustic features. When we considered different categories of non-vocal behavior, our analyses revealed that mice in all postnatal age groups produce higher rates of isolation USVs during active non-vocal behaviors than when lying still. Moreover, rates of isolation USVs are correlated with the intensity (i.e., magnitude) of non-vocal body and limb movements within a given trial. In contrast, USVs produced during different categories of non-vocal behaviors and during different intensities of non-vocal movement do not differ substantially in their acoustic features. Our findings suggest that levels of behavioral arousal contribute to within age variability in rates, but not acoustic features, of mouse isolation USVs.
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Humans are extraordinarily social, and social isolation has profound effects on our behavior, ranging from increased social motivation following short periods of social isolation to increased anti-social behaviors following long-term social isolation. Mice are frequently used as a model to understand how social isolation impacts the brain and behavior. While the effects of chronic social isolation on mouse social behavior have been well studied, much less is known about how acute isolation impacts mouse social behavior and whether these effects vary according to the sex of the mouse and the behavioral context of the social encounter. To address these questions, we characterized the effects of acute (3-day) social isolation on the vocal and non-vocal social behaviors of male and female mice during same-sex and opposite-sex social interactions. Our experiments uncovered pronounced effects of acute isolation on social interactions between female mice, while revealing more subtle effects on the social behaviors of male mice during same-sex and opposite-sex interactions. Our findings advance the study of same-sex interactions between female mice as an attractive paradigm to investigate neural mechanisms through which acute isolation enhances social motivation and promotes social behavior.
