Drug addiction results in part from maladaptive learning, including the formation of strong associations between the drug and the circumstances of consumption. However, drug-induced changes in gene expression underlying the saliency of these associations remain understudied. Consolidation of explicit memories occurs within the hippocampus, and we have shown that spatial learning induces expression of the transcription factor ⌬FosB in hippocampus and that this induction is critical for learning. Drugs of abuse also upregulate ⌬FosB in hippocampus, but the mechanism of its induction by cocaine and its role in hippocampus-dependent cocaine responses is unknown. We investigated differences in mouse dorsal and ventral hippocampal ⌬FosB expression in response to chronic cocaine, because these regions appear to regulate distinct cocaine-related behaviors. We found that cocaine-mediated induction of ⌬FosB was subregion-specific, and that ⌬FosB transcriptional activity in both the dorsal and ventral hippocampus is necessary for cocaine conditioned place preference. Further, we characterize changes in histone modifications at the FosB promoter in hippocampus in response to chronic cocaine and found that locus-specific epigenetic modification is essential for FosB induction and multiple hippocampusdependent behaviors, including cocaine place preference. Collectively, these findings suggest that exposure to cocaine induces histone modification at the hippocampal FosB gene promoter to cause ⌬FosB induction critical for cocaine-related learning.

Introduction Limbic predominant age related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is a recently characterized brain disease that mimics Alzheimer's disease (AD) clinically. To date, LATE‐NC is difficult to diagnose antemortem using clinical information or biomarkers. Recent studies suggest concentrations of extracellular vesicle (EVs) protein cargo derived from neuronal and glial cells may serve as useful diagnostic biomarkers for AD and other neurodegenerative diseases. Methods TDP‐43 was evaluated in neuronal (NDEVs), astrocyte (ADEVs), and microglial derived extracellular vesicles (MDEVs). EV preparations were isolated from the plasma of research subjects with autopsy‐confirmed diagnoses, including many with LATE (n = 22). Quantified TDP‐43 concentrations were compared to the cohort that included healthy controls, mild cognitively impairment (MCI), and AD dementia with diagnoses other than LATE‐NC (n = 42). Results TDP‐43 was significantly elevated in plasma ADEVs derived from autopsy confirmed LATE‐NC subjects, with or without comorbid AD pathology. Measurable levels of TDP‐43 were also detected in EV‐depleted plasma; however, TDP‐43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE‐NC. No correlation was observed between EV TDP‐43 levels with cognition‐based variables, sex, and APOE carrier status. Discussion Blood‐based EVs, specifically measuring TDP‐43 accumulation in ADEVs, may serve as a potential diagnostic tool to rapidly identify subjects who are currently living with LATE‐NC.

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The AP1 transcription factor ΔFOSB, a splice variant of FOSB, accumulates in the brain in response to chronic insults such as exposure to drugs of abuse, depression, Alzheimer's disease and tardive dyskinesias, and mediates subsequent long-term neuroadaptations. ΔFOSB forms heterodimers with other AP1 transcription factors, e.g. JUND, that bind DNA under control of a putative cysteine-based redox switch. Here, we reveal the structural basis of the redox switch by determining a key missing crystal structure in a trio, the ΔFOSB/JUND bZIP domains in the reduced, DNA-free form. Screening a cysteine-focused library containing 3200 thiol-reactive compounds, we identify specific compounds that target the redox switch, validate their activity biochemically and in cell-based assays, and show that they are well tolerated in different cell lines despite their general potential to bind to cysteines covalently. A crystal structure of the ΔFOSB/JUND bZIP domains in complex with a redox-switch-targeting compound reveals a deep compound-binding pocket near the DNA-binding site. We demonstrate that ΔFOSB, and potentially other, related AP1 transcription factors, can be targeted specifically and discriminately by exploiting unique structural features such as the redox switch and the binding partner to modulate biological function despite these proteins previously being thought to be undruggable.

INTRODUCTION: Limbic predominant age related TDP-43 encephalopathy (LATE) is a recently characterized brain disease that mimics Alzheimers disease (AD) clinically. To date, LATE is difficult to diagnose antemortem using clinical information or biomarkers. Recent studies suggest concentrations of exosomal protein cargo derived from neuronal and glial cells may serve as useful diagnostic biomarkers for AD and other neurodegenerative diseases. METHODS: TDP-43 was evaluated in neuronal (NDE), astrocyte (ADE), and microglial derived exosomes (MDE). Exosome preparations were isolated from the plasma of research subjects with autopsy-confirmed diagnoses, including many with LATE. Quantified TDP-43 concentrations were compared to cohort that included healthy controls, mild cognitively impairment (MCI), and AD dementia with diagnoses other than LATE. RESULTS: TDP-43 was significantly elevated in plasma ADEs derived from autopsy confirmed LATE-NC subjects, with or without comorbid AD pathology. Measurable levels of TDP-43 were also detected in exosome depleted plasma; however, TDP-43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE-NC. No correlation was observed between exosomal TDP-43 levels with cognition-based variables, sex, and APOE carrier status. DISCUSSION: Blood-based exosomes, specifically measuring TDP-43 accumulation in ADEs, may serve as a powerful diagnostic tool to rapidly identify subjects who are currently living with LATE-NC.