Interdisciplinary Neurobiology and Model Systems
As a group, the Feng and Fu teams’ focus is to translate genetic findings of neuropsychiatric disorders into neurobiological mechanisms and facilitate the development of therapeutics. Their research so far has made major advances in understanding the cellular physiology and circuitry mechanisms that underlie neuropsychiatric disorders — in particular, autism spectrum disorder (ASD), schizophrenia, and attention-deficit/hyperactivity disorder (ADHD) — with the state-of-the-art combinations of behavior, circuits, physiology, and genetics.
Synapse and Circuit Physiology
The main goal of the Synapse and Circuit Physiology team is to understand how synapse and circuit functions are perturbed and the role of such perturbation in neuropsychiatric disorders such as ASD, schizophrenia and ADHD. Studies mainly involve comprehensive electrophysiological assessments ranging from classical to optical electrophysiological techniques. They are working to pinpoint the neuronal circuits involved in neuropsychiatric disorders and to ultimately provide insights into the search for electrophysiological biomarkers and novel effective treatments for the disorders.
New Developmental Disease Models
This team focuses on the creation of new animal disease models for understanding the pathological mechanisms of brain disorders and the development of new approaches to effective treatment. With the development of new genome engineering technologies such as CRISPR, it is becoming increasingly feasible to apply these molecular tools in a wider range of species. The team is characterizing and developing genetic models of social, learning, and other behaviors in different animals.
The vector engineering team at the Stanley Center for Psychiatric Research, led by Ben Deverman, is interested in creating viral tools that enable more efficient and selective expression of genes in defined cell types in the brain. The group focuses mostly on adeno-associated viruses (AAVs), which have become a widely used and versatile platform for gene delivery to the brain due to their low immunogenicity and ability to provide long-term gene expression. AAVs allow researchers to test hypotheses about gene and cell function by expressing, knocking down, or editing genes of interest in vivo and by monitoring or modulating the state of specific cell populations using a rapidly expanding collection of genetically encoded sensors and actuators. In addition, AAVs are also being developed and used as gene therapy vehicles.
The group applies a variety of high-throughput selection and screening techniques to customize AAV capsids and recombinant genomes for targeting specific cell types and circuits. Through internal technology development and collaborations with fellow Stanley Center scientists, the vector engineering team supports disease model studies aimed at identifying new effective treatments for psychiatric disorders.
The goal of the Fishell laboratory is to understand how the vast variety of inhibitory interneuron subtypes are generated and how they subsequently integrate into the wide array of neural circuits that are embedded in different brain structures. Through exploring the molecular control of these events, it has become clear that perturbation of this process can result in a variety of brain dysfunctions including autism spectrum disorder (ASD), intellectual disability (ID) and schizophrenia. A new and growing interest in the laboratory is therefore aimed at seeing if better understanding of these developmental events can lead to the discovery of new treatments for these disorders.
The recent explosion in psychiatric disease genetics has revealed many genes likely to be involved in these debilitating disorders, and resulted in exciting glimpses of molecular pathways emerging from the data (e.g., chromatin remodeling and synaptic transmission). While such examples illustrate how some risk genes interact at the level of proteins to form networks involved in diverse areas of neurobiology, most of the identified genes do not fall into any well-defined cellular pathway. It is now clear that the biology also includes largely uncharted and incomplete networks that are probably unique to the human brain. This is a key bottleneck towards biological insight and therapeutic intervention.
Lage’s group works with collaborators in the Stanley Center to overcome these challenges through an integrative approach that leverages recent genetic discoveries in combination with large-scale proteomics experiments to derive human brain networks (of physically interacting proteins) perturbed by genetics in psychiatric diseases. The project sits at the inflection point of transformative technologies in stem cells, proteomics, genetics, and computational biology that have just become mature. An important aspect of the work is to establish robust statistical and technological approaches to integrate cell-type-specific protein networks and genetic data. Overall, the goal is to use recent genetic data to map, validate, and follow up on the brain-specific cellular networks perturbed by genetics in psychiatric diseases.
The Levin lab is dedicated to bringing the most appropriate transcriptomics technology solutions to answer important questions in biology. Over the last 10 years, the lab has pioneered new RNA-Seq methods and made definitive and comprehensive comparisons of available methods to guide this highly dynamic field. The team is interested in understanding the genetic and biochemical mechanisms underlying psychiatric disorders such as autism in the mammalian brain using single-cell genomics and transcriptomics. By deploying the most powerful, and often newest, technology to study these biological systems, and by collaborating with other Stanley Center scientists, the group aims to shed light on devastating — and in many cases currently incurable — brain disorders.
The brain is composed of a remarkably diverse set of cells, many of whose functions have only begun to be explored. The Macosko lab develops new genomics technologies to identify these novel populations, characterize their roles within normal circuitry, and understand how they contribute to disease states in pathological contexts.
Furthermore, the team is developing and deploying cutting-edge molecular techniques to more deeply understand the function of cellular specialization in the nervous system. In particular, the team seeks clear, actionable explanations for how the cells of the brain go awry in major mental illness.
The research in the Stevens laboratory is devoted to understanding the mechanisms by which neuron-glia and neural immune interactions facilitate the formation, elimination, and plasticity of synapses in heath and disease. In particular, the lab is focused on the role of microglia and the classical complement cascade in synaptic pruning and circuit refinement using a combination of molecular, electrophysiological, biochemical, and high-resolution imaging approaches in several model systems. A deep understanding of the mechanisms by which these pruning pathways are regulated and dysregulated in the developing brain could provide new insight into novel biomarkers and therapies in neuropsychiatric, neurodegenerative, and other brain diseases.