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Synaptic Tagging and Capture: From Synapses to Behavior

Periodic Reporting for period 4 - STC (Synaptic Tagging and Capture: From Synapses to Behavior)

Reporting period: 2020-10-01 to 2022-03-31

What is the problem/issue being addressed? How does an emotionally charged event lead to an unmemorable event becoming a permanent memory by virtue of temporal linkage?

Why is it important for society? In daily life we experience trivial events that we can recall temporarily but that gradually fade from our memory. However, when a salient event occurs before or after an insignificant event, we are able to recall details from the insignificant event which otherwise would have been forgotten. There is a tremendous survival benefit to this. We can detect subtle signals for a threat that may lie around the corner, because we still remember the details of our previous experience. However, the downside to this mechanism can be seen in post-traumatic stress disorders, where a traumatic event can haunt a person for life. I hope, and expect, that this work will establish a more firm base of our understanding of the role of synaptic plasticity in memory; from such a base we may be able to understand and treat better neuropsychological diseases thought to be related to aberrations in synaptic plasticity, such as post-traumatic stress disorder, schizophrenia, substance abuse disorders and dementia.

What are the overall objectives? In this grant, I aim to test two explicit predictions of a dominant model in the field of memory and learning known as Synaptic Tagging and Capture (STC model): 1) A naturally formed short-term memory can be stabilized by induction of heterosynaptic late-long term potentiation (L-LTP). 2) This stabilization is caused by the protein synthesis feature of L-LTP.
A) We were able to develop a method to optically activate two populations of neurons, at the cell body, independently. This is based on the co-expression of a red-shifted ChR2 (Chrimson) and a chloride channel (GtACR2). We tested the system, in drosophila, and it has been remarkably successful in drosophila; only a red-light, and not blue light, is able to activate the circuit in this system. We also tested this method in organotypic brain slices with equally successful result. The next step is to apply our method in behaving rodents. B) We used red-shifted ChR2 with a chemogenetic system, known as DREAD. In organotypic brain, we were able to effectively block the blue-induced activation of the neurons co-expressing red-shifted ChR2 and hM4D(Gi) (the receptor used in DREAD system). We have used this system in vivo with a comparable efficiency. In a collaboration with our colleagues at NIH, we included a part of in vivo data in a manuscript that is now under review. as and C) We were able to generate an optically induced weak fear memory in mice that lasts 15-30 minutes but not 24 hrs. To our best knowledge, there is no published work demonstrating induction of a fear weak memory, which last only for about 30min. Fear memory as we are all aware is a memory that is very difficult to forget. So, it is no surprise that making a fear memory that last only for a couple of minutes has been a challenge, which I believe that we overcome. D) We have shown that we can label newly synthesized proteins in vivo with L-azidohomoalaine amino acid. With this system, we were able to purify newly synthesized proteins from synaptic preparations. We were able to label newly synthesized proteins, in vivo as well. This is done by supplementing L-azidohomoalaine amino acid in animals diet. The next step is to induce a protein-synthesis dependent LTP in anesthetized animals that are fed with this diet and send the protein preps to the lab of Dr. Yates at the university of California, San Diego for mass spectrometry analysis. E) We developed a photoactivatable unnatural amino acid. This is to identify newly synthesized proteins that are believed to be essential for the stabilization of a memory. Currently, we are working to improve this system for the use in in vivo studies.
1) By the end of the project, we expect to have achieved the final two aims of this project: A) Examine the long-term behavioral impact of L-LTP protocol delivered to a sensory inputs on the stability of the short-term tone induced fear memory; B) Examine the electrophysiological impact of different in vivo conditioning protocols on synaptic transmission measured in vitro and in vivo.

2) We expect to have provided the proteomic landscape of the synapses that have gone through potentiation during an LTP and/or memory formation.

3) We also expect to have a system that allows to identify the upstream regions that send aversive signals (foot-shock) to the amygdala during cued fear memory formation.
synaptic plasticity underlies an associative memory