Sapna Sinha (Boyden Lab)

Title: Optogenetics Translation in Neuronal and Non-Neuronal cell population in the Periphery

Abstract: Foreign genes, such as microbial-derived optogenetic proteins, hold transformative potential for treating neurological disorders. However, immune response to these therapeutic transgenes compromises their long-term efficacy. This challenge is particularly pronounced in the peripheral nervous system (PNS), where neurons lack the protection of the blood-brain barrier (BBB). Here, we present an integrated approach to expand optogenetic control into both neuronal and non-neuronal cell populations of the periphery. First, we employ localized delivery strategies to achieve spatially confined expression within peripheral circuits and neuronal cell types of interest. Second, we leverage AI-guided de-immunization pipelines to redesign optogenetic proteins with reduced immunogenicity for application in non-neuronal cell population. Together, these innovations open a path toward precise and durable optogenetic modulation in peripheral tissues, with implications for studying brain–body communication and developing novel therapeutic interventions.

Md Rezaul Islam (Tsai Lab)

Title: Single Nuclei Transcriptomic and Genomic Landscape of Sensory-Evoked Gamma Stimulation 

Abstract: Sensory-evoked gamma stimulation has shown beneficial effects in Alzheimer’s disease. Emerging evidence suggests that neuropeptide(s) such as vasoactive intestinal peptide (VIP) may contribute partly to these effects. However, a systematic analysis of other neuromodulators involved in induced plasticity, and of the specific cell circuits, particularly at the subtype level, remains unknown. In this study, we exposed young wild-type mice to multiple visual stimulation frequencies, including 40 Hz, for one hour and performed single-nucleus transcriptomic profiling of the visual cortex and hippocampus. Analysis of more than 100,000 single nuclei revealed that transcriptomic changes were more pronounced in the visual cortex than in the hippocampus, with 40 Hz stimulation inducing specific alterations in neuromodulatory gene expression. Several of these candidates were validated using fiber photometry and biosensor(s), confocal imaging, and ELISA. Functional silencing of neuromodulatory hub genes upregulated by 40 Hz stimulation impaired cognitive performance, underscoring their critical role in learning and memory. Further analysis revealed that a somatostatin-expressing interneuron subtype was selectively responsive to 40 Hz stimulation, implicating this circuit in frequency-specific plasticity. Chronic three-week stimulation further modulated gene expression changes in this interneuron subtype, highlighting their potential relevance in sensory-evoked gamma stimulation. Furthermore, single-nucleus multi-ome profiling identified 40 Hz–associated candidate cis-regulatory elements (cCREs) across multiple cell types. Together, these findings provide the first integrated transcriptomic and epigenomic landscape of sensory-evoked gamma stimulation, revealing key neuromodulators and cell-subtype–specific responses that likely drive its associated cellular plasticity.