Project Details
Description
Abstract:
Deficits in learning and memory are hallmarks of several psychiatric disorders including
schizophrenia, autism, and Alzheimer’s. These cognitive processes in both normal and disease
states are controlled by spatiotemporally regulated genes in neuronal circuits. Studies have
implicated the role of immediate-early genes (IEGs), particularly, Activity-regulated cytoskeletal
associated (Arc/Arg3.1) in behavioral responses. Arc has garnered special interest because it
affects synaptic transmission, plasticity and long-term memory. The conversion from short-term
to long-term memory, a process known as consolidation, requires Arc protein levels to be
maintained over several hours to days. However, existing studies indicate very short half-lives of
Arc mRNA and protein (less than 60 mins). It is intriguing how short temporal window of Arc
expression promotes memory consolidation over long time scales. For IEGs including Arc, the
regulation of gene expression initiates at the level of transcription. Therefore, we hypothesize that
periodic cycles of transcription in a subset of neurons would enable persistence of Arc levels in
the network for stabilizing the memory trace. We propose to identify the molecular mechanisms
underlying these transcription cycles. Recently, we have generated a knock-in mouse model
where the endogenous Arc gene is fluorescently labeled with bacteriophage-derived stem loops,
enabling high detection sensitivity and imaging of individual Arc alleles in single neurons over
several hours with unprecedented temporal resolution. By real-time imaging of endogenous Arc
gene transcription in cultured neurons and in acute hippocampal slices, we will establish the long-
term Arc transcription dynamics and its dependence on patterns of neuronal activity. We will
characterize the role of activity and translational feedback in Arc transcriptional regulation at
different time scales. This will provide insights into: i) how long term Arc transcriptional regulation
impacts memory consolidation and ii) improve design of activity-based reporters to reliably
correlate Arc expression and behavior.
Status | Active |
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Effective start/end date | 3/15/21 → 2/28/23 |
Funding
- NATIONAL INSTITUTE OF MENTAL HEALTH: $436,800.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $226,800.00
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