BAF53b, a Neuron-Specific Nucleosome Remodeling Factor, Is Induced after Learning and Facilitates Long-Term Memory Consolidation.

Although epigenetic mechanisms of gene expression regulation have recently been implicated in memory consolidation and persistence, the role of nucleosome-remodeling is largely unexplored. Recent studies show that the functional loss of BAF53b, a postmitotic neuron-specific subunit of the BAF nucleosome-remodeling complex, results in the deficit of consolidation of hippocampus-dependent memory and cocaine-associated memory in the rodent brain. However, it is unclear whether BAF53b expression is regulated during memory formation and how BAF53b regulates fear memory in the amygdala, a key brain site for fear memory encoding and storage. To address these questions, we used viral vector approaches to either decrease or increase BAF53b function specifically in the lateral amygdala of adult mice in auditory fear conditioning paradigm. Knockdown of Baf53b before training disrupted long-term memory formation with no effect on short-term memory, basal synaptic transmission, and spine structures. We observed in our qPCR analysis that BAF53b was induced in the lateral amygdala neurons at the late consolidation phase after fear conditioning. Moreover, transient BAF53b overexpression led to persistently enhanced memory formation, which was accompanied by increase in thin-type spine density. Together, our results provide the evidence that BAF53b is induced after learning, and show that such increase of BAF53b level facilitates memory consolidation likely by regulating learning-related spine structural plasticity.SIGNIFICANCE STATEMENT Recent works in the rodent brain begin to link nucleosome remodeling-dependent epigenetic mechanism to memory consolidation. Here we show that BAF53b, an epigenetic factor involved in nucleosome remodeling, is induced in the lateral amygdala neurons at the late phase of consolidation after fear conditioning. Using specific gene knockdown or overexpression approaches, we identify the critical role of BAF53b in the lateral amygdala neurons for memory consolidation during long-term memory formation. Our results thus provide an idea about how nucleosome remodeling can be regulated during long-term memory formation and contributes to the permanent storage of associative fear memory in the lateral amygdala, which is relevant to fear and anxiety-related mental disorders.

Specific disruption of contextual memory recall by sparse additional activity in the dentate gyrus.

The dentate gyrus (DG) of the hippocampus is essential for contextual and spatial memory processing. While lesion or silencing of the DG impairs contextual memory encoding and recall, overly activated DG also prevents proper memory retrieval. Abnormally elevated activity in the DG is repeatedly reported in amnesic mild cognitive impairment (aMCI) patients or aged adults. Although the correlation between memory failure and abnormally active hippocampus is clear, their causal relationship or the underlying nature of such interfering activity is not well understood. Using optogenetics aided by a carefully controlled adeno-associated virus infection system, we were able to examine the differential effects of abnormally activated hippocampus on mice motor behavior and memory function, depending on the extent of the stimulation. Optogenetic stimulation of massive proportion of dorsal DG cells resulted in memory retrieval impairment, but also induced increase in general locomotion. Random additional activity in a sparse population of dorsal DG neurons, however, interfered with contextual memory recall without inducing hyperactivity. Our findings thus establish the causal role of elevated DG activity on memory recall failure, suggesting such aberrant DG activity may contribute to amnesic symptoms in aMCI patients and aged adults.

Synaptic plasticity-dependent competition rule influences memory formation.

Memory is supported by a specific collection of neurons distributed in broad brain areas, an engram. Despite recent advances in identifying an engram, how the engram is created during memory formation remains elusive. To explore the relation between a specific pattern of input activity and memory allocation, here we target a sparse subset of neurons in the auditory cortex and thalamus. The synaptic inputs from these neurons to the lateral amygdala (LA) are not potentiated by fear conditioning. Using an optogenetic priming stimulus, we manipulate these synapses to be potentiated by the learning. In this condition, fear memory is preferentially encoded in the manipulated cell ensembles. This change, however, is abolished with optical long-term depression (LTD) delivered shortly after training. Conversely, delivering optical long-term potentiation (LTP) alone shortly after fear conditioning is sufficient to induce the preferential memory encoding. These results suggest a synaptic plasticity-dependent competition rule underlying memory formation.

Turnover of fear engram cells by repeated experience.

A sparse population of neurons active during a learning event has been identified as memory engram cells. However, cells that are recruited to support memory when experience is repeated have been scarcely explored. Evidence from previous studies provides contradictory views. To address these questions, we employed learning-dependent cell labeling in the lateral amygdala (LA) and applied electrophysiological recording, spine imaging, and optogenetic tools to the labeled neurons with or without retraining. We found that engram cells established from original fear learning became dispensable for memory retrieval specifically with relearning, and this correlated with a reduction of synaptic transmission and loss of dendritic spines in these neurons. Despite such decreased connectivity, direct activation of these neurons resulted in fear-memory recall. We further identified that repeated memory was encoded in neurons active during relearning. These results suggest a shift in neuronal ensembles encoding fear memory in the LA by relearning through disconnection of the existing engram neurons established from original experience.