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Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this work, a methodology for assessing the impact of implantation surgery on laboratory mice on behavior was created. The study included the design of several implants fabricated on various printed circuit board (PCB) technologies with overall diameters between 26-28mm and weights between 4.5-6.5g. 11 adult CD1 mice were implanted with the devices and their behavior was analyzed using common behavioral benchmark tests. The results show that implants designed to be 10% of the animal's body weight showed no adverse effects on mobility or social behavior. These results illustrate a method to identify and reduce the adverse behavioral changes inherent to device implantation. Additional considerations for implant surgery are provided. These results are validated with the implantation of a Bluetooth Low Energy (BLE) wireless sensor tag. The implanted wireless tag showed an average Received Signal Strength Indicator (RSSI) of 62.96dBm with a standard deviation of 4.95dBm and a variance of 24.5 dBm 2 . The high RSSI and variance values show that the implant was working well inside of the mouse's body and that the mouse was fully recovered and readily exploring its surroundings.Clinical Relevance-This work 1) studies the behavioral impact of implantable wireless biopotential devices. This will help clinical researchers conducting behavioral studies using sensor implants. 2) demonstrates a working implanted BLE wireless model inside of a mouse. Various wireless connectivity metrics are studied.

The transcription factor ΔFosB has been proposed as a molecular switch for the transition from casual, volitional drug use into a chronically addicted state, but the upstream regulatory mechanisms governing ΔFosB expression are incompletely understood. In this study, we find a novel regulatory role for the transcription factor E2F3, recently implicated in transcriptional regulation by cocaine, in controlling ΔFosB induction in the mouse nucleus accumbens (NAc) following cocaine administration. We find that an E2F consensus sequence 500 bp upstream of the Fosb transcription start site is enriched for E2F3 specifically over other E2F isoforms. We further conclude that ΔFosB expression is regulated specifically by E2F3a, not E2F3b, that E2f3a expression is specific to D1 receptor-expressing medium spiny neurons, and that E2F3a overexpression in NAc recapitulates the induction of Fosb and ΔFosb mRNA expression observed after chronic cocaine exposure. E2F3a knockdown in NAc does not abolish ΔFosb induction by cocaine, a result consistent with previously published data showing that singular knockdown of upstream regulators of ΔFosB is insufficient to block cocaine-induced expression. Finally, to elucidate potential combinatorial epigenetic mechanisms involved in E2F3a's regulation of Fosb , we explore H3K4me3 enrichment at the Fosb promoter and find that it is not enhanced by E2F3a overexpression, suggesting that it may instead be a pre-existing permissive mark allowing for E2F3a to interact with Fosb . Together, these findings support a role for E2F3a as a novel, upstream regulator of the addiction-mediating transcription factor ΔFosB in NAc.