The role of ventral hippocampal engrams in healthy and disease states
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Citation
Abstract
Memories can be imbued with positive and negative emotions. The ventral hippocampus (vHPC) is known for its ability to process this positive and negative information and to relay it to its downstream targets. By combining multiple activity-dependent tagging strategies, we have been able to visualize components of memory’s physical manifestation (i.e., a memory engram) within the vHPC, and have found that it parses differentially valenced information into two discrete populations of cells. Additionally, these cells have different transcriptomic and methylation patterns, different terminal projection patterns, and drive behavior differentially. Moreover, we identified that a subpopulation of genes associated with neurodegeneration, such as Amyloid Precursor Protein (APP) and Apolipoprotein E (APOE), were specifically upregulated and positive engrams and downregulated in negative engrams. Interestingly, we found that genes associated with neuroprotection, such as BDNF and Pin1, were upregulated in reward and downregulated in shock engrams. This led to our hypothesis that memory-related stress is sufficient to induce neurodegeneration. Therefore, we next asked whether chronic stimulation of a negative engram in an aged mouse could induce neurodegenerative or tau-like pathology. We found that these mice had numerous behavioral deficits and strong physiological changes through histological changes in p-tau, neurofibrillary tangle expression, and changes in microglia and astrocyte quantity and morphology. Together, the compiled data show that the vHPC is embedded with both positive and negative engrams, and specifically, when these negative engrams are in a hyperactive state, they can induce systems-wide changes that are detrimental for overall brain and behavioral health.