Biology subjects

Rao, B. Y.

Publications and source records attributed to Rao, B. Y..

3 recordsLinked to original sources

bioRxiv2026

A transcriptomic axis aligns with in vivo functional dynamics in hippocampal inhibitory circuits

Linking molecular identity to function in vivo at single-cell resolution remains an outstanding challenge in neuroscience. Here, we bridge this gap in the mouse hippocampus with an end-to-end pipeline of cell-resolved two-photon imaging and spatial transcriptomics. CA1 interneurons exhibiting heterogeneous physiological responses during a virtual-reality navigation task were post hoc clustered by gene expression into 5 GABAergic subclasses and 14 types. Physiological responses of individual cells aligned with a transcriptomic axis, and a classifier trained on physiological features alone recovered the same ordered organization. Our approach establishes a direct, scalable framework for linking in vivo circuit dynamics to constituent cell identity, revealing a transcriptomic axis that encompasses the structural and functional diversity of hippocampal inhibitory neurons. One-Sentence SummaryTracking neurons from behavior to spatial transcriptomics links in vivo function to molecular identity in the hippocampus.

neuroscience↗

bioRxiv2025

Rare mutations implicate CGE interneurons as a vulnerable axis of cognitive deficits across psychiatric disorders

Neuropsychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia (SCZ) share genetic risk factors, including genes affected by rare high-penetrance single nucleotide variants (SNVs) and copy number variants (CNVs). ASD and SCZ exhibit both overlapping and distinct clinical phenotypes. Cognitive deficits and intellectual disability--critical predictors of long-term outcomes--are common to both conditions. To investigate shared and disorder-specific neurobiological impact of highly penetrant rare mutations in ASD and SCZ, we analyzed human single-nucleus whole-brain sequencing data to identify strongly affected brain cell types. Our analysis revealed caudal ganglionic eminence (CGE)-derived GABAergic interneurons as a key nexus for cognitive deficits across these disorders. Notably, genes within 22q11.2 deletions, known to confer a high risk for SCZ, ASD, and cognitive impairment, showed a strong expression bias toward vasoactive intestinal peptide-expressing cells (VIP+) among CGE subtypes. To explore perturbations of VIP+ GABAergic interneurons in the 22q11.2 deletion syndrome in vivo, we examined their activity in the Df(16)A+/- mouse model during a spatial navigation task and observed reduced activity along with altered responses to random rewards. At the population level, VIP+ interneurons exhibited impaired spatial encoding and diminished subtype-specific activity suggesting deficient disinhibition in CA1 microcircuits in the hippocampus, a region essential for learning and memory. Overall, these results demonstrate the crucial role of CGE-derived interneurons in mediating cognitive processes that are disrupted across a range of psychiatric and neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

2P-NucTag: on-demand phototagging for molecular analysis of functionally identified cortical neurons

Neural circuits are characterized by genetically and functionally diverse cell types. A mechanistic understanding of circuit function is predicated on linking the genetic and physiological properties of individual neurons. However, it remains highly challenging to map the molecular properties onto functionally heterogeneous neuronal subtypes in mammalian cortical circuits in vivo. Here, we introduce a high-throughput two-photon nuclear phototagging (2P-NucTag) approach for on-demand and indelible labeling of single neurons via a photoactivatable red fluorescent protein following in vivo functional characterization in behaving mice. Using this novel function-forward pipeline to selectively label and transcriptionally profile previously inaccessible place and silent cells in the hippocampus of behaving mice, we identify unexpected differences in gene expression between these hippocampal pyramidal neurons with distinct spatial coding properties. Thus, 2P-NucTag opens a new way to uncover the molecular principles that govern the functional organization of neural circuits. One-Sentence Summary2P-NucTag - A novel high-throughput on-demand phototagging approach to identify selective gene expression of functionally distinct neurons in vivo in behaving animals.

neuroscience↗