Stability of Odor Representations in the Olfactory Tubercle

/ABSTRACT The brain’s ability to maintain stable internal representations of the external world is critical for consistent behavior. Yet recent studies show that neural representations can gradually shift over time, a phenomenon known as representational drift. While initially observed in associative areas like the hippocampus and parietal cortex, drift also occurs in primary sensory regions such as the piriform cortex, a main site of olfactory identity processing. This challenges our understanding of how stable odor-guided behaviors persist despite ongoing neural change. The olfactory tubercle (OT) receives direct input from the olfactory bulb and dopaminergic input from the ventral tegmental area (VTA), positioning it as a site where odor identity and reward value may be integrated to support stable representations. However, it remains unclear whether OT representations are stable or flexible, how they change with learning, and what role dopamine plays in this process. This project will investigate the temporal dynamics of odor representations in the OT and test whether dopamine contributes to their stability or flexibility. By conducting this work in the Molecular and Cellular Biology department at Harvard University, I will be supported by world-class resources and mentorship to elucidate the mechanisms underlying odor representation dynamics in the following aims. In Aim 1, I will use miniscope calcium imaging in behaving mice to track OT population activity during a two-alternative forced choice (2AFC) odor discrimination task. I will assess whether odor representations remain stable during continual reinforcement or drift when reinforcement is paused. I will then test whether new odors disrupt existing representations, and whether removing odors from training accelerates drift. In Aim 2, I will selectively ablate VTA-derived dopamine inputs to the OT using 6-hydroxydopamine (6-OHDA) and examine how this affects drift. I will assess whether dopamine stabilizes representations during extended training or protects against drift when cue-outcome training is paused. Finally, I will test whether dopamine depletion impairs or enhances the incorporation of new odor information, shifting the balance between flexibility and stability in the OT. Across both aims, I will use statistical and computational tools, including similarity metrics, dimensionality reduction, and decoding models, to quantify drift and uncover its structure. This work will advance our understanding of how the brain preserves meaningful sensory representations and how dopamine shapes the trade-off between stability and adaptability. The activities in this grant will anchor my training in systems and computational neuroscience and prepare me for a successful research career. To further my development as an independent scientist, I will supplement this training by presenting my work at national and international conferences, publishing my findings in peer-reviewed journals, and by training the next generation of scientists through teaching and mentorship. Project Number: 1F31DC023435-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Deafness and Other Communication Disorders (NIDCD) | Principal Investigator: Hannah McCalmon | Institution: HARVARD UNIVERSITY, CAMBRIDGE, MA | Award Amount: $46,145 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F02B-H (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31DC02343501