Session 6

Individual differences in cognition and responses to neuromodulation treatments depend on distributed brain network functions and the anatomy that support them. Over 5 years of Early Independence Award support, our laboratory has clarified the basis of executive functions in joint anatomical-functional brain network and linked models of network controllability to variability in neuromodulation outcomes. In addition, we have clarified the psychological mediators of neuroethical choices that the public makes about whether to use neuromodulation. Collectively, these lines of inquiry have revealed the promises and pitfalls in imaging-guided neuromodulation for executive functions and when the public might accept specific uses of technology. Here, we will share the key findings from our research program in personalized neuromodulation for frontal lobe functions and the context of public attitudes in which they exist.

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During multicellular development, spatial position and lineage history play powerful roles in controlling cell fate decisions. Using a serine integrase-–based recording system, we engineered cells to record lineage information in a format that can be read out in situ. The system, termed intMEMOIR, allowed in situ reconstruction of lineage relationships in cultured mouse cells and flies. intMEMOIR uses an array of independent three-state genetic memory elements that can recombine stochastically and irreversibly, allowing up to 59,049 distinct digital states. It reconstructed lineage trees in stem cells and enabled simultaneous analysis of single- cell clonal history, spatial position, and gene expression in Drosophila brain sections. These results establish a foundation for microscopy-readable lineage recording and analysis in diverse systems.

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The biology and behavior of adults differ from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific isolation to identify the transcriptomes of C. elegans' four major tissues (or "tissue-ome"), identifying ubiquitously expressed and tissue-specific "enriched" genes, and tissue-specific alternative splicing. These data reveal the hypodermis' metabolic character, suggest potential worm-human tissue orthologies, and identify tissue-specific changes in the Insulin/IGF-1 signaling pathway. Finally, we developed a machine learning-based prediction tool for 76 sub-tissue cell types, which we used to predict cellular expression differences in IIS/FOXO signaling, stage-specific TGF-β activity, and basal vs. memory-induced CREB transcription. Together, these data provide a rich resource for understanding the biology governing multicellular adult animals.
Recently, we discovered that exposure to purified small RNAs isolated from pathogenic Pseudomonas aeruginosa is sufficient to induce pathogen avoidance in the treated worms and in four subsequent generations of progeny. The RNA interference and PIWI-interacting RNA (piRNA) pathways, the germline, and the ASI neuron are required for avoidance behavior induced by bacterial small RNAs, and for the transgenerational inheritance of this behavior. A single P. aeruginosa non-coding RNA, P11, is both necessary and sufficient to convey learned avoidance of PA14, and its C. elegans target, maco-1, is required for avoidance. These memories can be transferred to naïve animals via Cer1 retrotransposon-encoded capsids. Cer1 functions to transmit information from the germline to neurons and is required for C. elegans' learned avoidance ability and transgenerational inheritance. C. elegans has co-opted a potentially dangerous retrotransposon to protect itself and its progeny from a common pathogen.

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