Periodic Reporting for period 4 - DimorphicCircuits (Elucidating the development of sexually-dimorphic circuits: from molecular mechanisms to synapses and behavior)
Periodo di rendicontazione: 2024-04-01 al 2024-09-30
When evolutionary paths taken by each sex within a given species diverge, the result is behavioral differences that promote specific fitness outcomes for each sex. Despite five decades of research into the link between genes, circuits, and behavior, the molecular and synaptic mechanisms that give rise to sexually dimorphic nervous systems remain poorly understood. Our proposed research plan, DimorphicCircuits, was designed to expand knowledge on neuronal circuit development, in general, and on how sexual identity is represented in neuronal circuits to control dimorphic behavioral output, in particular. We have developed a unique system that enables the study of sexual dimorphism at the synaptic, circuit, genetic, and behavioral levels across all developmental stages. Central to this proposal is the exploration of how sex-shared neurons morph into sexually dimorphic circuits that produce varied behaviors in males and hermaphrodites. Our detailed analyses at synaptic resolution reveal how variations in connectivity contribute to significant behavioral differences. Key findings include the dimorphic propagation of mechanosensory information, the dimorphic connectivity that controls sexually dimorphic nociceptive behaviors, and the discovery of sex-specific neuromodulatory mechanisms that preserve these dimorphic states, which are essential for survival and reproductive success.
As part of this project, our lab has made significant strides in molecular neurobiology, detailing how genetic sex influences neuronal circuit assembly and function. Our transcriptomic-based approaches have yielded a developmental atlas of gene expression that highlights critical periods where sex-specific genes dictate circuit differentiation. These molecular insights are crucial for understanding the developmental and the evolutionary aspects of neuronal function. Whole-animal transcriptomics throughout development and single-cell neuronal transcriptomics data sets generated during this project provide a strong framework to investigate novel molecular determinants of dimorphic properties, with a future focus on conserved genes that could contribute to the proper function of the nervous system.
As part of this project, our lab has made significant strides in molecular neurobiology, detailing how genetic sex influences neuronal circuit assembly and function. Our transcriptomic-based approaches have yielded a developmental atlas of gene expression that highlights critical periods where sex-specific genes dictate circuit differentiation. These molecular insights are crucial for understanding the developmental and the evolutionary aspects of neuronal function. Whole-animal transcriptomics throughout development and single-cell neuronal transcriptomics data sets generated during this project provide a strong framework to investigate novel molecular determinants of dimorphic properties, with a future focus on conserved genes that could contribute to the proper function of the nervous system.
Overview of Work and Objectives
The project, DimorphicCircuits, aimed to elucidate the development of sexually dimorphic neural circuits, spanning molecular mechanisms to synaptic functionality and behavior. Key objectives included exploring circuit topology's role in behavior, synaptic basis for dimorphic circuits, and genetic mechanisms influencing sex-specific neural development.
Key Achievements
1. Dimorphic Circuit Function and Behavioral Insights:
-Objective 1: Explored avoidance behavior, mechanosensation and the integration of spatially opposing cues. Studies revealed that differences in neural circuit topology are sufficient to drive sexually dimorphic behaviors in C. elegans.
-Results:
-Published findings in Current Biology (2021), Nature Communications (2022), and Cell Reports (2023).
-Presentations at international conferences, including FENS-Kavli, EMBO workshops, and Cold Spring Harbor Laboratory meetings.
-Novel Methodologies: Developed a microfluidic device for dual spatial cue integration, advancing neural activity monitoring.
2. Synaptic and Genetic Mechanisms:
-Objective 2: Investigated sex-specific synaptic pruning and dimorphic synapse formation using trans-synaptic labeling techniques.
-Results:
-Identified hermaphrodite-specific synaptic connections during development.
-Insights published in Nature Communications (2024).
3. Comprehensive Gene Expression Atlas:
-Objective 3: Generated a sex-specific gene expression atlas across developmental stages.
-Results:
-Published in Nature Communications (2024).
-Database accessible online, facilitating community-wide research advancements.
4. Significant Innovations:
Developed protocols to isolate male populations of C. elegans with over 98% purity.
Innovations in imaging techniques for high-resolution analysis of specific neuronal substructures.
Exploitation and Dissemination
1. Scientific Contributions:
-Advanced understanding of how neural circuits adapt to environmental and genetic factors to produce sexually dimorphic behaviors.
-Published five significant papers, hosted a project website, and developed methodologies beneficial to broader neuroscience research.
2. Training and Educational Impact:
-Trained a multidisciplinary team, contributing to their career advancement in academia and industry.
3. Outreach and Societal Impact:
-Promoted awareness of sex differences in neuroscience through public workshops, international conferences, and media engagement.
The project, DimorphicCircuits, aimed to elucidate the development of sexually dimorphic neural circuits, spanning molecular mechanisms to synaptic functionality and behavior. Key objectives included exploring circuit topology's role in behavior, synaptic basis for dimorphic circuits, and genetic mechanisms influencing sex-specific neural development.
Key Achievements
1. Dimorphic Circuit Function and Behavioral Insights:
-Objective 1: Explored avoidance behavior, mechanosensation and the integration of spatially opposing cues. Studies revealed that differences in neural circuit topology are sufficient to drive sexually dimorphic behaviors in C. elegans.
-Results:
-Published findings in Current Biology (2021), Nature Communications (2022), and Cell Reports (2023).
-Presentations at international conferences, including FENS-Kavli, EMBO workshops, and Cold Spring Harbor Laboratory meetings.
-Novel Methodologies: Developed a microfluidic device for dual spatial cue integration, advancing neural activity monitoring.
2. Synaptic and Genetic Mechanisms:
-Objective 2: Investigated sex-specific synaptic pruning and dimorphic synapse formation using trans-synaptic labeling techniques.
-Results:
-Identified hermaphrodite-specific synaptic connections during development.
-Insights published in Nature Communications (2024).
3. Comprehensive Gene Expression Atlas:
-Objective 3: Generated a sex-specific gene expression atlas across developmental stages.
-Results:
-Published in Nature Communications (2024).
-Database accessible online, facilitating community-wide research advancements.
4. Significant Innovations:
Developed protocols to isolate male populations of C. elegans with over 98% purity.
Innovations in imaging techniques for high-resolution analysis of specific neuronal substructures.
Exploitation and Dissemination
1. Scientific Contributions:
-Advanced understanding of how neural circuits adapt to environmental and genetic factors to produce sexually dimorphic behaviors.
-Published five significant papers, hosted a project website, and developed methodologies beneficial to broader neuroscience research.
2. Training and Educational Impact:
-Trained a multidisciplinary team, contributing to their career advancement in academia and industry.
3. Outreach and Societal Impact:
-Promoted awareness of sex differences in neuroscience through public workshops, international conferences, and media engagement.
DimorphicCircuits has significantly advanced the state of the art by uncovering fundamental mechanisms underlying sexually dimorphic neural circuit function and development. It demonstrated that differences in circuit topology alone can drive sexually dimorphic behaviors, resolving debates about the contributions of circuit architecture versus sensory input. This work also revealed how the mechanosensory circuit in C. elegans displays sex-specific design, with molecular and structural distinctions shaping behavior. By showing that small-scale synaptic rewiring can reprogram behaviors without altering sensory input, the project challenges existing paradigms in neuroscience. These findings, coupled with the development of novel methodologies such as high-precision microfluidics and advanced imaging techniques, provide unprecedented insights into the genetic and molecular basis of dimorphic circuit formation.