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.
A precise temporal control of activated-regulated gene expression is an essential element of memory formation, and cognitive functions. Dysregulated expression of one such gene, Arc, has been implicated in memory deficits, altered cognitive performance and linked to several psychiatric disorders including schizophrenia, autism, and Alzheimer's. Therefore, understanding the dynamics of Arc gene expression and its regulation over time by imaging gene behavior will allow us to design optimal time windows of Arc level manipulations to ensure memory consolidation.
