Sequential Transcriptional Gates in The Thalamo-Cortical Circuit Coordinate Memory Consolidation

<p>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—<em>Camta1</em> and <em>Tcf4 </em>in the ANT, and <em>Ash1l</em> 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, <em>Camta1</em> was required for initial memory maintenance over days, while <em>Tcf4</em> and the histone methyl-transferase, <em>Ash1l</em>, 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 <em>Camta1</em> primarily targets genes involved in synaptic plasticity, while <em>Tcf4</em> regulates genes associated with longer-lived adhesion and structural elements. <em>Ash1l </em>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year dc:date.available

2025

Author dc:creator

• Terceros, Andrea

Contributors dc:contributor

• Priya Rajasethupathy

• long-term memory
• thalamo-cortical circuit
• transcriptional regulation
• memory consolidation
• CRISPR
• ChIP-seq
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/827

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1831