Understanding how the brain stably maintains a memory trace for years has significant implications for a variety of neuropsychiatric disorders, from age-related cognitive decline to addiction and post-traumatic stress disorder (PTSD). Yet, despite the clear clinical importance, the field's understanding of memory maintenance is in its infancy. While thousands of mechanisms for how a memory initially forms have been identified, only three storage mechanisms are known. This is important, as recent findings indicate that identification of unique mechanisms governing the storage of pathogenic memories provides targets for their selective erasure. There is a growing consensus that memory is supported by structural and functional plasticity at excitatory synapses on dendritic spines, with tight regulation of the actin cytoskeleton providing the scaffolding. microRNAs, endogenous RNAs that act as translational repressors, have a flexibility and wide genomic range that suggests their bidirectional modulation may be a mechanism capable of coordinating the complexity required for the brain to maintain the structural integrity of a long-lasting memory trace. Additional preliminary data in this proposal from microRNA expression profiling indicates that regulation of the actin cytoskeleton is the most significant pathway associated with the microRNAs persistently altered one month after learning in the amygdala, the brain's emotional memory center and a critical participant in PTSD. Thus, the central hypothesis driving this proposal is that microRNAs contribute to the long-term stability of a memory trace by maintaining learning-induced structural plasticity. In addition, the proposed experiments will investigate the microRNA profile of a PTSD-like memory, guided by the hypothesis that the persistence of a traumatic memory is subserved by the recruitment of an additional, unique set of microRNAs within the amygdala. Similar to the selective disruption of a drug-associated memory that has been achieved, the current goal is to identify unique mechanisms that can be exploited to erase a traumatic memory. This proposal details an innovative approach to understanding how microRNAs and their post-transcriptional targets contribute to the long-term maintenance of a memory within the amygdala. A multidisciplinary, in vivo approach will be utilized to achieve the primary goals of this project: (1) To determine the impact of persistent microRNA changes on the maintenance of a remote (30-day old) memory and structural plasticity. (2) To determine the functional impact of persistent microRNA changes unique to the maintenance of a traumatic memory. The proposed work will establish the microRNA profile governing traumatic and non-traumatic memory storage and establish their functional impact on memory, structural plasticity, actin dynamics and the post-translational targets. By unifying two areas of intense research, nuclear and synaptic mechanisms of memory, we expect this proposal to identify novel mechanisms participating in the long-term, structural stabilization of a memory trace, as well as a set of unique microRNAs that, when targeted, will enable selective erasure of a PTSD-like memory.
The public health relevance of the proposed research is two-fold: (1) The work is expected to greatly improve our understanding of how the brain stores memory for weeks to months in the face of constant protein turnover. These targets can then be exploited to preserve fading memory, such as with age-related cognitive decline. (2) This work is further expected to identify novel regulators of traumatic, PTSD-like memory that can be exploited to selectively erase the memory, without altering other, non-traumatic memories. Taken together, this will make a significant contribution to the mission of NIMH to develop effective treatments for mental illness.
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