2026 Theses Doctoral

Bridging Neuronal Identity and Function of the Hippocampal CA1 Region in Health and Disease

Rao, Bovey Y.

The hippocampal CA1 region plays a central role in episodic and spatial memory. However, how its diverse neuronal population contributes to circuit computation remains incompletely understood. Moreover, it is unclear how genetic perturbations alter defined microcircuit interactions to produce cognitive dysfunction. This dissertation examines how neuronal identity shapes CA1 microcircuit dynamics and develops experimental and analytical approaches to directly link functional activity with molecular definition.

To address these questions, I combined in vivo optical physiology, molecular characterization, transcriptomic profiling, and computational image analysis.

Using three-dimensional acousto-optic deflector two-photon calcium imaging, I recorded activity from large populations of CA1 GABAergic interneurons in behaving mice during spatial navigation tasks, followed by post hoc immunohistochemical identification of molecular subtypes. These approaches were applied in the Df(16)A+/- mouse model of the 22q11.2 deletion syndrome to determine how genetic haploinsufficiency alters inhibitory microcircuit dynamics.

To directly link functional dynamics and gene expression, I developed 2P-NucTag, an in vivo phototagging strategy that enables activity-guided labeling of physiologically characterized neurons for downstream transcriptional and electrophysiological analyses.

To support downstream spatial transcriptomic analysis, I also devised a non-parametric vignetting correction algorithm to improve quantitative reliability in sparse spatial transcriptomic imaging datasets.

I found that CA1 inhibitory interneurons exhibit structured, subtype-specific dynamics during spatial behavior and that genetic haploinsufficiency selectively disrupts coordination among these populations without grossly altering subtype abundance. I further demonstrated that functional identity can be directly coupled to transcriptional profiling. Finally, I showed that computational correction enhances the accuracy and interpretability of spatial gene expression quantification. Together, these results advance methodological and mechanistic understanding of how neuronal identity relates to circuit function in health and disease.