Student Theses and Dissertations
Date of Award
2025
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Priya Rajasethupathy
Keywords
long-term memory, thalamo-cortical circuit, transcriptional regulation, memory consolidation, CRISPR, ChIP-seq
Abstract
How are memories maintained over weeks, months or even years? The molecular mechanisms that enable memories to persist over long time-scales remain poorly understood. As a point of entry, recent work in our lab revealed that beyond the hippocampus, where memories are initially formed over hours/days, the thalamo-cortical circuit is important for the gradual stabilization of memories over weeks/months. In this thesis, I aimed to reveal the molecular mechanisms operating in the thalamo-cortical circuit that may be responsible for extending memory time-scales. I began by developing a virtual reality-based behavioral paradigm where, by varying the frequency of learned associations, mice formed multiple memories but only consolidated some, while forgetting others, over the span of weeks. I then profiled the molecular programs that diverge between consolidated and forgotten memories across the anterior thalamus (ANT) and anterior cingulate cortex (ACC). Transcriptomic analyses identified distinct waves of transcription (cellular macrostates), unique to consolidated memories, that defined memory persistence. Notably, a select set of transcriptional regulators—Camta1 and Tcf4 in the ANT, and Ash1l in the ACC—orchestrated region specific molecular programs that enabled entry into these macrostates. Targeted CRISPR-knockout studies revealed that while these transcriptional regulators had no effects on memory formation, they had prominent time-dependent roles in memory stabilization. In particular, Camta1 was required for initial memory maintenance over days, while Tcf4 and the histone methyl-transferase, Ash1l, were required for sustaining memory at later stages, extending into weeks. How might these transcription factors function to extend memory time-scales? Further mechanistic studies through ChIP-sequencing revealed that Camta1 primarily targets genes involved in synaptic plasticity, while Tcf4 regulates genes associated with longer-lived adhesion and structural elements. Ash1l epigenetically regulates both synaptic and structural gene programs, thus functioning not necessarily to create new targets but rather to "prime" and prolong pre-existing plasticity and structural gene programs required for synaptic persistence. This study highlights the ANT–ACC circuit as a crucial circuit for memory maintenance and puts forth a model where transcriptional programs acting on progressively longer time-scales across the ANT-ACC support continuous memory stabilization ultimately shaping stable cortical memory ensembles.
License and Reuse Information
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Terceros, Andrea, "Sequential Transcriptional Gates in The Thalamo-Cortical Circuit Coordinate Memory Consolidation" (2025). Student Theses and Dissertations. 827.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/827
Comments
A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy