Periodic Reporting for period 1 - swim2limb (Development and Evolution of Tetrapod Motor Circuits)
Reporting period: 2022-09-01 to 2025-02-28
A hallmark of the nervous system is its rich cell-type diversity and intricate patterns of connectivity and activity. Behavior largely is an emergent property of this complexity. Thus, to understand behavior, we must define neuron’s molecular, cellular and functional properties. This task has proven especially challenging for motor circuits: with readily apparent output patterns of motor activity; yet, astonishingly heterogeneous populations of neurons. To parse this complexity, I propose a novel approach harnessing the unique behavioral switch during Xenopus frog metamorphosis. This transition from simple swimming to more complex, coordinated limb movement offers an ideal opportunity to study the expansion and diversification of two motor circuits in one organism. I aim to identify and compare fundamental principles of motor circuit organization and function. First, I will define the molecular, functional and behavioral features of swim-to-limb circuit complexification (Aim 1)—a crucial step in developing this new model of motor circuit diversity. Next, I will identify the developmental mechanisms that drive this profound change in circuit composition and output, and evaluate the contribution of increasing cellular heterogeneity to pre- and post-metamorphic neuron activity and behavior (Aim 2). Finally, to define the conserved and divergent circuit features for swimming and walking across evolution, I will expand to a cross-species approach comparing frogs/mice and fish/tadpoles (Aim 3). These intra- and inter- species comparisons will deepen our understanding of the drivers of tetrapod motor complexity and its relationship to motor circuit composition and output. My findings will carry beyond motor circuits, defining generalizable mechanisms of development and function of nervous system heterogeneity that may even become applicable in clinical settings.
I will exploit the swim-to-walk transition of frog metamorphosis and vertebrate evolution, and harness recent breakthroughs in the sequencing6 and genetic perturbation7 of Xenopus, to build a developmental, molecular and functional understanding of the cellular and circuit changes that underlie tetrapod motor behavior (Fig. 2).
Aim 1 OBSERVE. Define molecular, functional and behavioral transformation of spinal circuits during frog metamorphosis. We will be the first to determine how cardinal and sub-cardinal classes of spinal neurons vary in their molecular profile for swimming and walking in a metamorphosing tadpole, and how this molecular variation corresponds with differences in motor circuit activity and behavior.
Aim 2 PERTURB. Use frog metamorphosis to identify the mechanism and function of swim-to-walk motor circuit complexification. Our unique approach will test whether neural diversity for tetrapod movement derives from differences in proliferation or patterning, transcriptional networks, and/or neural activity. It positions us to resolve how neuron, circuit and behavioral changes relate.
Aim 3 COMPARE. Classify conserved or divergent cell types of swim and limb circuits over vertebrate evolution. By comparing fish/tadpole and mouse/frog, we will reveal conserved molecular and cellular architecture of swim/walk circuits and variation in this architecture for species-specific behavior.
Aim 1 OBSERVE. Define molecular, functional and behavioral transformation of spinal circuits during frog metamorphosis. We will be the first to determine how cardinal and sub-cardinal classes of spinal neurons vary in their molecular profile for swimming and walking in a metamorphosing tadpole, and how this molecular variation corresponds with differences in motor circuit activity and behavior.
Aim 2 PERTURB. Use frog metamorphosis to identify the mechanism and function of swim-to-walk motor circuit complexification. Our unique approach will test whether neural diversity for tetrapod movement derives from differences in proliferation or patterning, transcriptional networks, and/or neural activity. It positions us to resolve how neuron, circuit and behavioral changes relate.
Aim 3 COMPARE. Classify conserved or divergent cell types of swim and limb circuits over vertebrate evolution. By comparing fish/tadpole and mouse/frog, we will reveal conserved molecular and cellular architecture of swim/walk circuits and variation in this architecture for species-specific behavior.
Our dissection of swim and limb circuits will contribute fundamental insights into the role of cell-type heterogeneity in motor physiology and behavior, the developmental mechanisms that differentiate motor circuits for variant locomotion, and the molecular driving forces of circuit evolution. It will define generalizable developmental and evolutionary mechanisms that drive cell-type heterogeneity and pinpoint the significance of this heterogeneity for neural circuit output.