Weizhe Hong, Ph.D. - US grants

A confluence of technologies is transforming the biological, environmental, and social sciences into data-intensive sciences. Indeed, with the data now produced every day, there exists an unprecedented opportunity to revolutionize the journey of scientific discovery. By harnessing these data, one can advance the understanding of human conditions, behaviors, and their underlying mechanisms and social outcomes, enabling a spectrum of new and transformative research and practice. Fundamental new approaches across computing, mathematics, engineering, and sciences are critically needed, and future scientists must be accordingly trained in these emergent cutting-edge methods. This National Science Foundation Research Traineeship (NRT) award to the University of California, Los Angeles will address this demand by training graduate students at the intersections of data science, mathematics, cryptography, artificial intelligence, genomics, behavior science, and social science. The traineeship program anticipates training one hundred twenty (120) PhD students, including fifty (50) funded trainees, from the social, biological, mathematical and computational sciences and engineering, through a unique and comprehensive training opportunity.

This cross-disciplinary traineeship program has four research areas: genomics and genetics; brain imaging and image analysis; mobile sensing and individual behaviors; and social networks. These areas are interconnected through three core themes: mathematical modeling and network analysis, scalable machine learning and big data analytics, and biomedical applications and social outcomes. At the nexus of these research areas and core themes, this traineeship program provides novel interdisciplinary graduate education to advance both graduate student training and scientific research. Key features of the traineeship include novel curricula; cross-disciplinary laboratory rotations between engineering, life science, and social science; new foundational classes at the intersections of data science, mathematics, artificial intelligence, behavior science, and social science; summer internships at research institutes, big data firms, and hospitals and translational clinical settings; career, ethics, and technical communication skills development; and outreach to minority, women, and high school students with a distinct focus on groups traditionally underrepresented in STEM PhD programs.

The NSF Research Traineeship (NRT) Program is designed to encourage the development and implementation of bold, new potentially transformative models for STEM graduate education training. The program is dedicated to effective training of STEM graduate students in high priority interdisciplinary research areas through comprehensive traineeship models that are innovative, evidence-based, and aligned with changing workforce and research needs.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Project Summary/Abstract Impairments in social functioning is a prominent, debilitating symptom in many neuropsychiatric disorders, such as autism spectrum disorders, schizophrenia, and major depressive disorder. Currently the neural underpinnings of these social deficits are poorly understood, and effective therapeutic approaches are still lacking. Elucidation of the neural circuit mechanisms for social behaviors will improve our understanding of the disease mechanisms of neuropsychiatric disorders, facilitating the development of potent treatments. Parenting behavior is a prevalent and evolutionarily ancient social behavior that critically affects the survival and well-being of the offspring in a wide range of animal species from invertebrates to humans, and is characterized by remarkable differences between different sexes and reproductive states. Although parenting behavior is thought to be controlled by evolutionarily conserved neural circuits, the nature and functions of these circuits remain largely undefined. Furthermore, the neural mechanisms regulating the differential display of parenting behavior in different sexes and physiological states are poorly understood. Unraveling these questions will provide key insights into the neural circuit mechanisms underlying parenting behavior and the basic principles governing the regulation of sexually dimorphic behaviors. Such insights will improve our understanding on the regulation of human social behaviors in both health and disease. Recently, we have uncovered novel functional roles for GABAergic neurons in the mouse medial amygdala (MeA) in controlling parenting behavior in females and infanticidal and parenting behaviors in males. We have also comprehensively identified molecularly heterogeneous GABAergic subpopulations in both male and female MeA. These findings open up a unique opportunity for an in-depth dissection of the functional organization of a brain area newly identified to critically control parenting and infanticidal behaviors. Using a combination of cutting-edge functional manipulation and imaging techniques, we aim to develop a novel mechanistic model for how differential activations of distinct GABAergic subpopulations in the MeA regulate opposing pup-directed behaviors. We will address a series of important questions central to this model: (1) Are parenting and infanticidal behaviors controlled by different or the same MeA GABAergic subpopulations (Aim 1)? (2) What are the downstream neural circuits of MeA GABAergic neurons that mediate parenting and infanticidal behaviors (Aim 2)? (3) How are parenting and infanticidal behaviors encoded by neural activity patterns in MeA GABAergic subpopulations and efferent projections (Aim 3)? To answer these questions, we will perform precise, functional manipulations of genetically and projection-defined MeA GABAergic subpopulations and their axonal projections, and examine the neural activity dynamics of MeA GABAergic subpopulations and their projections in freely behaving animals during native pup-directed behaviors. Together, investigation of this model will yield key, novel insights into the neural circuitry governing affiliative and agonistic behaviors towards pups and the general principles underlying the control of sexually dimorphic social behaviors.

Summary The mammalian central nervous system supports a multitude of cognitive and behavioral functions through coordinated action of different neural circuits that are composed of diverse sets of differentiated cell types, including both neurons and non-neuronal cells. Glial cells are essential constituents of the brain and play vital roles in the development and function of the neural circuits. Compared to neurons, however, glial cells have been understudied in the past. One significant hurdle is the limited tools and technologies to precisely target and manipulate these cells in vivo. Novel AAV-based CRISPR technologies have recently been developed in the Chen lab that enables high-throughput, direct in vivo gene editing in the mouse brain. Furthermore, a new single-cell RNA sequencing (scRNA-seq) method, Act-seq, has recently been developed in the Hong lab that enables faithful characterization of cell types and detection of rapid transcriptional changes at the level of single cells. The proposed project will build upon the strong expertise of the two labs to further develop innovative technologies to provide a powerful toolbox for editing, labeling, manipulating, and profiling of specific types of glial cells in vivo. Aim 1 will develop, optimize and validate AAV-based CRISPR technology for direct in vivo tagging, labeling, and functional manipulation of glial cells in the mammalian brain. Aim 2 will develop, optimize, and validate single-cell RNA-seq technology for faithful transcriptional profiling of glial cell types and accurate detection of their transcriptional changes in response to physiological and genetic perturbations. Finally, Aim 3 will combine CRISPR technology with scRNA-seq for multiplexed gene editing and transcriptome profiling of glial cells in vivo at single-cell level. The development and combination of the above two new technologies will empower the versatile targeting, identification, and manipulation of glial cells and open multiple new directions. Establishment of these tools will offer new capabilities to rapidly gain insights into glial cells' compositions, functions, and interplay with neurons for better dissection of neural circuits and understanding of complex behaviors.

Abstract: Attachment powerfully shapes our development and remains a primary driver of health and well-being in adulthood; disruption of attachments is highly traumatic. While affiliation, defined as general positive social interactions, is shared widely among mammals, attachment, or selective affiliation as a result of a bond, is far rarer and of primary relevance to humans. While affiliation has been studied in a number of contexts, how the neural circuitry that underlies affiliation ultimately contributes to adult attachment remains largely unknown. In this proposal, we will take a comparative framework to understand how the basic circuitry and neuronal patterns that underlie non-selective affiliation are ultimately engaged and underlie selective attachment in adulthood. Specifically, we will examine how the neurobiology of affiliative behavior in mice has been elaborated to support the more complex attachments formed by monogamous prairie voles and gregarious fruit bats, representing a spectrum of social relationships. We will focus on the hippocampal CA2 region as it has been shown to play a specialized role in social behavior and receives direct inputs from oxytocin and vasopressin producing cells in the paraventricular hypothalamus. Specifically, we will test the overarching hypothesis that CA2 population activity patterns follow similar trajectories across species before and during mating, and subsequently diverge to causally drive affiliative investigation in mice (Golshani/Hong) and different forms of attachment in prairie voles (Donaldson) and bats (Yartsev). To test this hypothesis we will refine and use new generation open-source wireless miniaturized microscopes (Aharoni) that will allow prolonged recordings of large neuronal populations in freely behaving animals. Kennedy will bring computational expertise and allow a unified data analysis framework cross species. In Aim 1 we will perform in-vivo calcium imaging in mice, prairie voles and bats to test the hypothesis that mating experiences modulate CA2 neural dynamics and that CA2 activity patterns encode spatial and identity information. We hypothesize that species that form attachments to mating partners, activity patterns will differentiate preferred vs. non-preferred partners. In Aim 2 we will use chemogenetic inhibition of CA2 in all species to determine whether CA2 causally drives affiliative and attachment behaviors. In Aim 3 we will test the hypothesis that inhibition of vasopressin inputs to CA2 will reduce the dimensionality of CA2 population activity patterns after mating, diminish memory of the mate in all species, and in voles and bats, reduce the decodability of the identity of the previous mating partner. In a technology development aim, we will develop and test a ?true wireless? digital data transmitting microscope with power over distance charging capability that will allow prolonged imaging over many hours without human intervention.