Anterior Cingulate Function Across Multiple-Time Scales Shapes Learning and Memory

Author

Josue Manuel Regalado

Date of Award

2023

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Rajasethupathy Laboratory

Abstract

We are constantly learning from our everyday experiences about the people we are with, the things we do,where we are, and how we feel. If deemed significant enough,we may choose to remember what we learn for the rest of our lives.For my doctoral work, I studied how a part of the neocortex, the anterior cingulate cortex (ACC),has critical functions across multiple time-scales,from minutes to days-long learning,to weeks-long memory consolidation.The prefrontal cortex, and particularly the ACC portion, is known to be important for goal-directed learning, especially as the relationship between our actions (including effort) and their outcomes (including value) has to be continually adjusted to maximize rewards. To gain mechanistic insight not how ACC facilitates such goal-directed learning, I designed a behavioral task in which mice self-initiate trials to learn various cue- reward contingencies. By performing brain recordings as they perform this task, I found that ACC encodes and facilitates an extended motivational state, including trial history, reward outcome, and vigor to initiate the next trial, that together leads to maximization of rewards and improved learning. To determine how ACC inherits these signals, I recorded from inputs to ACC and identified a ramp in bulk neural activity in OFC-to-ACC that continued to rise as mice traversed non-rewarded rooms, which peaked when they finally reached a rewarded room, thus maintaining an extended motivational state. Cellular resolution imaging of OFC further confirmed these neural correlates of motivation, and further delineated separate ensembles of neurons that sequentially tiled the ramp. Together, these results identify a mechanism by which OFC maps out task structure to extend motivation and trains ACC in the development of a learned goal-directed behavior. As learned representations become episodic memories, their initial encoding is thought to occur in the hippocampus. However, overtime, it is thought that memories become less reliant on the hippocampus and consolidated in the neocortex for long-term stabilization. Despite extensive phenomenological study, we still lack mechanistic understanding of this brain-wide reorganization process. To provide insights, we developed a behavioral task where mice consolidate some (highly salient) memories, while forgetting others (less salient), and recorded brain activity in hippocampus, cortex, and intervening circuits throughout weeks-long memory consolidation. Initial bulk neural activity recordings during behavior identified a unique and significant neural correlate of memory in anterior thalamus that emerged in training and persisted for weeks. Inhibition of the anteromedial (AM) thalamic projection to ACC during training caused deficits in memory consolidation, whereas more strikingly, mild excitation was sufficient to enhance consolidation of otherwise unconsolidated (less salient) memories. We next developed a technique for imaging three brain regions simultaneously with single-cell resolution in the behaving mouse to gain mechanistic understanding into the role of anteromedial thalamus during consolidation. Using this technology, we found that while the hippocampus encodes low and high salient memories equally, the anteromedial thalamus forms preferential tuning to salient memories, and establishes long-ran synchrony with ACC that are causally required for stabilizing cortical representations to achieve successful memory consolidation. Thus, we extend previous models of memory consolidation to include AM as a critical mediator of long-term cortical storage. Overall, my thesis work has identified mechanisms, spanning diverse time-scales, by which ACC builds and sustains learned representations that can be used for long-term memory.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Regalado, Josue Manuel, "Anterior Cingulate Function Across Multiple-Time Scales Shapes Learning and Memory" (2023). Student Theses and Dissertations. 773.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/773