Asst. Prof. Dr. Lora B. Sweeney
The Sweeney Group utilizes evolution and development of vertebrates to link the composition of neural circuits to behavioral output. Focusing on movement, they apply two novel approaches to determine how motor circuits differ for swimming versus limb-based behavior. First, sampling across the vertebrate clade, they compare the composition and function of motor circuits in fish, amphibians and mammals. Such cross-species analysis reveals conserved circuit features preserved over hundreds of millions of years of evolution, and simultaneously identifies species-specific innovations critical for aquatic versus terrestrial motor output. Second, they exploit frog metamorphosis, in which a single organism transitions from tail- to limb-based behavior over developmental time, to dissect the cell types, circuits and functional elements of each movement pattern. With this combined evolutionary and developmental approach, their goal is to gain fundamental insight into the template of vertebrate behavior.
Focal points of interest
Inhibitory interneurons have been at the forefront of the Sweeney Lab for many years as critical players in the regulation of motor behavior. Classical perturbation experiments have shown they are necessary for proper frequency and coordination of motor output. Recent work from the Sweeney Lab has further prioritized inhibitory neurons as evolutionarily-conserved regulators of complex behavior. They have found that inhibitory neurons are some of the most diverse neuronal types in mammals, comprising hundreds of transcriptionally-distinct subtypes, each with a largely unexplored function. They moreover show that these transcriptional distinctions are highly conserved in frogs that last shared a common ancestor with mammals 360 million years ago, but are absent in tadpoles. Thus, inhibitory neuron heterogeneity emerges as a specific feature of limb movement, underscoring its importance in complex behavior. Finally, in diseased mammalian motor circuits, they find select populations of inhibitory neurons are lost in high numbers at precisely the time of motor dysfunction. As such, understanding inhibitory neuron function in swim versus limb movement is one of their primary focuses.
Technical proficiency and instrumentation
The Sweeney Lab has deep expertise in the characterization and manipulation of neuronal cell types across species. This is exemplified by their leadership in the genetic and viral manipulation of frogs, achieving both spatial and temporal resolution with CRISPR-based loss-of-function and AAV-mediated circuit tracing. Additionally, they have polished methods for comparative cell type profiling in lesser-studied vertebrates, optimizing single cell sequencing and in situ gene expression analysis in the tadpole and frog, for example, and innovating computational approaches for distant mammalian-to-amphibian cross-species cell type comparisons. They combine these deep molecular and genetic studies with functional imaging and machine-learning based behavioral analyses. It is this breadth from genetics to behavior that defines the Sweeney Lab as a leader in cross-species and amphibian neuroscience, and optimally positions them to compare inhibitory neuron-derived neuropeptides, their circuits, and function across species.
Aspirations for the next 5 years
The Sweeney Lab aims to identify the most salient features of inhibitory neuron expression and circuit architecture that have stood the test of evolutionary time. Specifically, in tadpoles and frogs, they will profile inhibitory cell types that differ in their neuropeptide expression, and map the anatomy and connectivity of these circuits in the brain and spinal cord. This analysis in amphibians will serve as a rosetta stone to translate between invertebrate and vertebrate circuits across the Consortium, with the end goal to build a cross-species understanding of the species-shared and species-specific neuropeptide-ome of inhibitory networks in the central nervous system.
References
- Vijatovic D, Toma FA, Harrington ZPM, Sommer C, Hauschild R, Trevisan AJ, Chapman P, Julseth MJ, Brenner-Morton S, Gabitto MI, Dasen JS, Bikoff JB, Sweeney LB (2024) Spinal neuron diversity scales exponentially with swim-to-limb transformation during frog metamorphosis. bioRxiv 2024.09.20.614050. doi: 10.1101/2024.09.20.614050
- Jaeger ECB, Vijatovic D, Deryckere A, Zorin N, Nguyen AL, Ivanian G, Woych J, Arnold RC, Gurrola AO, Shvartsman A, Barbieri F, Toma FA, Cline HT, Shay TF, Kelley DB, Yamaguchi A, Shein-Idelson M, Tosches MA, Sweeney LB (2024) Adeno-associated viral tools to trace neural development and connectivity across amphibians. Developmental Cell, 1534–5807. doi: 10.1016/j.devcel.2024.10.025.
- Salamatina A, Yang JH, Brenner-Morton S, Bikoff JB, Fang L, Kintner CR, Jessell TM, Sweeney LB (2020) Differential loss of spinal interneurons in a mouse model of ALS. Neuroscience 450, 81–95.
