Wong, V. | Search bioRxiv

bioRxiv2018

Negative memory engrams in the hippocampus enhance the susceptibility to chronic social defeat stress

The hippocampus has been highly implicated in depression symptoms. Recent findings suggest that the expression and susceptibility of depression symptoms are related to the enhanced functioning of the hippocampus. We reasoned that hippocampal engrams, which represent ensembles of neurons with increased activity after memory formation, could underlie some contributions of the hippocampus to depression symptoms. Using the chronic social defeat stress (CSDS) model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor. TetTag mice were used to label social defeat-related hippocampal ensembles by LacZ. Engram cells correspond to ensembles that were reactivated by the same stressor.\n\nCompared to resilient and non-stressed control mice, we found that in both the dorsal and ventral hippocampal CA1 regions, susceptible mice exhibited a higher reactivation of social defeat-related LacZ-labeled cells (i.e. engram cells). The density of CA1 engram cells correlated with the level of social avoidance. Using DREADD to reactivate social defeat-related but not neutral contextual stimuli-related CA1 engram cells decreased social interaction. Increased engram cells in susceptible mice were region specific and could not be found in the dentate gyrus. Susceptible mice exhibited more negative stimuli-, but not neutral stimuli-, related CA1 engram cells than resilient mice in the dorsal hippocampus. Finally, chronic, but not a short and subthreshold, social defeat protocol was necessary to increase CA1 engram cell density. Together, our findings reveal that the susceptibility to CSDS is regulated by hippocampal CA1 engrams for negative memory. Hippocampal engrams for negative memory may underlie the vulnerability and expression of cognitive symptoms in depression.\n\nSignificance statementWe provided evidence that negative memory hippocampal engrams contribute to the susceptibility to developing depression-related behavior after chronic social defeat stress. The activation of positive memory engrams have been shown to alleviate depression-related behaviors, while our findings reveal the pathological roles of negative memory engrams that could lead to those behaviors. Increased negative memory engrams could be a downstream effect of the reported high hippocampal activity in animal models and patients with depression. Unlike affective symptoms, we know much less about the cellular mechanisms of the cognitive symptoms of depression. Given the crucial roles of hippocampal engrams in memory formation, enhanced reactivation of negative memory engrams could be an important cellular mechanism that underlies the cognitive symptoms of depression.

animal behavior and cognition↗

bioRxiv2017

PBAF’s genomic binding dynamics are regulated via bromodomain-acetyl-lysine interactions and select chromatin states

Transcriptional bursting involves genes rapidly switching between active and inactive states. Chromatin remodelers actively target arrays of acetylated nucleosomes at select enhancers and promoters to facilitate or shut down the repeated recruitment of RNA Pol II during transcriptional bursting. It is unknown how acetylated chromatin is dynamically targeted and regulated by chromatin remodelers such as PBAF. Thus, we sought to understand how PBAF targets acetylated chromatin using live-cell single molecule fluorescence microscopy. Our work reveals chromatin hubs throughout the nucleus where PBAF rapidly cycles on and off the genome. Deletion of PBAFs bromodomains impairs targeting, stable engagement and persistent binding on chromatin in hubs. Interestingly, PBAF has a higher probability to stably engage chromatin inside hubs indicating that hubs contain a unique nucleosomal scaffold compared to global chromatin. Dual color imaging of PBAF in hubs near H3.3 or HP1 reveals that PBAF targets both euchromatic and heterochromatic regions with distinct genome binding kinetics that mimic chromatin stability. Removal of PBAFs bromodomains stabilizes H3.3 and HP1 binding within chromatin indicating that bromodomains may play a direct role in remodeling of the nucleosome. Our data, suggests that PBAF differentially and dynamically engages a variety of chromatin structures involved in both activation and repression of transcription via bromodomains. Furthermore, PBAFs binding stability on chromatin may reflect the chromatin remodeling potential of different bound chromatin states. Statement of SignificanceTranscriptional bursting involves a gene rapidly switching between transcriptionally active and inactive states. To regulate transcriptional bursting, chromatin must interchange between euchromatin and heterochromatin to permit or restrict access of transcription factors including RNA Polymerase II to enhancer and gene promoters. However, little is known regarding how chromatin remodelers dynamically read a rapidly changing 4D epigenome. We used live-cell single molecule imaging to characterize the spatiotemporal chromatin binding dynamics of PBAF, a chromatin remodeler that accesses both euchromatin and heterochromatin to regulate transcription. PBAF cycles on and off chromatin hubs in select nuclear regions where it distinctly engages euchromatin and heterochromatin via bromodomains in its BAF180 subunit. Our study provides the framework to understand how the 4D epigenome is regulated.

cell biology↗