Molecular basis of social behavior

Sociality is an essential component of animal behavior, and its deficits are closely associated with mental illnesses in humans, such as autism spectrum disorder. At the organism level, the ethology of social behavior has long been investigated in various insects (e.g., bees and ants) and vertebrate species. Utilizing breakthrough technologies including optogenetics and calcium imaging, the neural basis of social behavior has been extensively studied in recent years as well, advancing our understanding of social behavior down to the circuit and cellular levels. In contrast, the task of unraveling the intricate molecular mechanisms that underlie the development and regulation of sociality, particularly in vertebrates, has proven to be exceedingly challenging.

The Geng lab is dedicated to uncovering the molecular basis of social behavior in vertebrate animals and its implications for human health and diseases. The right experimental model can significantly accelerate mechanism studies for complex biological phenomena such as social behavior, as exemplified by the role Drosophila played in the study of embryogenesis and C. elegans in apoptosis research. In the Geng lab, we developed a unique juvenile zebrafish model of sociality. Compared to its rodent counterparts, this model is amendable to high-throughput behavioral assays, rapidly develops robust social behavior in just 3 weeks, and can be easily manipulated experimentally by genetic, chemical, physical, and behavioral perturbations on a large scale. 

Using two behavioral assay platforms we developed for the juvenile zebrafish model, Fishbook and ZeChat, we routinely test up to 1000 fish per day, a throughput unprecedented in vertebrate social behavioral assays. 

Fishbook: Geng et al. Top2a promotes the development of social behavior via PRC2 and H3K27me3. Sci Adv. 2022. 

ZeChat: Geng et al. Social behavioral profiling by unsupervised deep learning reveals a stimulative effect of dopamine D3 agonists on zebrafish sociality. Cell Rep Methods. 2023.

Building on the model and methods developed in the lab, we continually innovate in both experimental and analytical approaches. We apply cutting-edge technologies, including high-throughput behavioral assays, high-throughput chemical screening, CRISPR/Cas9 gene editing, whole-brain neuroactivity imaging, single-cell multiomics, and machine learning, in our research to investigate the mysterious molecular underpinnings of sociality. Our long-term goal is to develop a new paradigm for social behavioral research by establishing an experimental framework for the systematic interrogation of its molecular mechanisms. 

Current research of the lab focuses on the following themes:

Genetic underpinnings of social behavior

Previously, in the absence of a simple genetic model of vertebrate sociality, the field had to rely almost exclusively on disease-centric epidemiology surveys to discover potential genetic determinants of sociality. An ongoing theme of our research is to develop new methodologies for large-scale exploration of the genetic networks underlying social behavior in the zebrafish model. 

Epigenetic regulations of social behavior

Research in eusocial insects such as ants and bees points to a profound regulatory role of the epigenome in behavioral development. However, how changes in epigenetic status modulate behavior in vertebrates is not well understood. A long-term interest of the lab is to investigate how epigenetic mechanisms influence social behavior, as well as the development of mental illnesses such as autism spectrum disorder. For example, we discovered that the polycomb repressive complex 2 (PRC2) and its associated histone mark, H3K27me3, are closely linked to the regulation of social behavior.

Environmental modulation of social behavior and autism

An estimated 40% of autism risk is contributed by environmental factors, yet we know very little about the nature of these risk factors. We use high-throughput chemical screening to systematically evaluate environmental chemicals for their impacts on social behavior and autism risk. Previously, we discovered a Top2a-PRC2-H3K27me3 pathway that acts as a sensor for environmental toxicants, coordinating the expression of numerous genes relevant to social behavior and autism.

Mapping out the social brain

Emerging evidence suggest that complex behaviors such as sociality are often controlled by coordinated activities across the entire brain, rather than by isolated neural circuits. Mapping out the key brain structures involved in these activities will help us connect molecular alterations with functional changes of the brain with social behavioral abnormalities relevant to mental illnesses. We are developing innovative approaches to map out brain-wide spatial and temporal activity dynamics that underlie various types of social behavior. 

Method development

We are actively developing high-throughput assays and high-resolution analysis methods to study various aspects of social behavior, along with other behaviors relevant to mental illnesses. Additionally, we are working on innovative whole-brain imaging methods and analysis pipelines to facilitate the assessment of neural activity changes in the context of molecular perturbations.

Translational research

Mental illnesses are not only among the most devastating and burdensome of all human diseases but are also some of the most poorly treated. We leverage our high-throughput behavioral assessment platforms for hypothesis-driven and screening-based translational discoveries. Examples include the discovery of pro-social effects of a PRC2 inhibitor and dopamine D3 receptor agonists.