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Our research is driven by insights from human genetics, which offer an unbiased starting point independent of specific hypotheses. Our efforts are informed by rare variant risk gene discovery work (i.e., and ) and common risk variants genetics findings spearheaded by Stanley Center Human Genetics groups. These genetic findings clearly show that neither schizophrenia nor bipolar disorder are caused by a single gene. Rather, mutations in numerous genes each make fractional contributions to these conditions that, in aggregate, significantly increase risk.

Identifying points of pathobiological convergence

In many instances, the biological functions of schizophrenia- and bipolar disorder-associated genes in the brain remain unclear, making it difficult to understand how their reduced expression contributes to disease biology. Additionally, little is known how clusters of these genes interact within broader systems in the brain to drive the complex biological processes underlying schizophrenia, bipolar disorder, and related illnesses. Each mutation may also have additional effects unrelated to its influence on these diseases. 

Thus, a key emphasis of the Stanley Center neurobiology program is to identify points of biological convergence across risk gene biology, which can also help in understanding the great majority of these disease cases where the specific genetic underpinning is unknown.

An interdisciplinary endeavor

To unravel these biological mechanisms and link schizophrenia and bipolar genetic variation with mental health outcomes, we are employing a multifaceted approach. Several animal models are being examined with molecular, neurophysiological and behavioral analyses to assess in vivo biology, while in vitro approaches include work with human stem cell-derived systems and direct analysis of human tissue and samples. This integrated approach relates molecular changes to cellular function to circuit interactions and behavioral outputs and, in the end, to promising therapeutic opportunities.

Addressing the complexity of psychiatric disease biology has often required building better tools, including precise, quantitative, and scalable ways to measure cellular and molecular phenotypes, and new techniques for manipulating biological systems. As such, the work of the Neurobiology program relies heavily on the efforts of teams in the Stanley Center actively engaged in tool development.

The Stanley Center neurobiology program is fortunate to be the cornerstone of the Program in Brain Health at the Ó³»­´«Ã½, embedding our efforts within a rich scientific environment with colleagues and collaborations across disciplines that helps support our program's goals.