May 13, 2022 / Neuroscience

The brain in order and (psychiatric) disorder

Josh Azevedo

Psychiatric disorders are exceptionally challenging to study and, for the millions who suffer from one, even more challenging to live with. Researchers around the world are studying these debilitating disorders to better understand their underlying biology, how they develop, and new avenues of treatment. We heard from a few of these researchers at our recent Psychiatric Disorders Research Symposium and wanted to highlight the ways they’re pushing new research frontiers in understanding the brain in health and psychiatric disorders.

The normal order of things: Tracing neurodevelopment

While most psychiatric disorders have both a genetic and an environmental component, some—such as schizophrenia—arise during development, when several neural progenitor cells develop into the hundreds of billions of cells in our brain. The development of these cells depends on a multitude of interdependent factors—gene expression signatures, cell–cell communication, and spatial context—and any error in these processes can disrupt brain function for life. But what does “normal” development look like?

To answer this question, Michael Ratz, PhD, from the Karolinska Institute and KTH Royal Institute of Technology used Chromium Single Cell and Visium Spatial Gene Expression technologies to trace brain development.

Using TREX (TRacking and gene EXpression) profiling, researchers barcoded and expressed EGFP in cells in the forebrain of embryonic mice, enabling them to track the fate of neural progenitor cells throughout development. They further built on this method with Space-TREX, which incorporates spatial transcriptomics to enable the simultaneous tracking of gene expression and cell lineage in whole tissue sections. Combining these approaches, researchers were able to obtain high-resolution, high-throughput reconstructions of cell lineages, fates, and tissue architecture in the developing brain.

Watch how they did it and discover how these methods can give us better insights into both healthy and abnormal brain development in Dr. Ratz’s on-demand presentation. Watch now →

Characterizing the transcriptional underpinnings of schizophrenia

Even among psychiatric disorders, schizophrenia is considered extremely genetically heterogeneous. To try and get a clearer picture of the genetic antecedents of this disorder, W. Brad Ruzicka, MD, PhD, from McLean Hospital used single nuclei RNA sequencing (snRNA-seq) of the prefrontal cortex in patients with schizophrenia and controls.

His group made the remarkable finding that 77% of differentially expressed genes (DEGs) in schizophrenia were downregulated; of these, 94% were in neurons. Looking at gene ontology, these DEGs converged on neuron-relevant biological processes; however, even in single cells, patient transcriptomes were very heterogeneous. There were patients with schizophrenia that seemed more transcriptionally similar to controls, and controls that were similar to schizophrenia.

To address this heterogeneity, they developed the transcriptional pathology score (TPS) where each cell type was graded based on its similarity to control or schizophrenia patients, then each cell type was averaged for an aggregate TPS. This methodology not only consistently separated two schizophrenia subtypes across multiple patient cohorts, but was also associated with a transcriptionally defined cell state Dr. Ruzicka’s group identified.

Learn more about Dr. Ruzicka’s methodology and how his group’s work is dissecting the transcriptional underpinnings of schizophrenia in the on-demand webinar. Watch now →

Moving forward

We sincerely appreciate all the presenters and attendees who made the Psychiatric Disorders Research Symposium such a success, and we thank you for your willingness to share your work and your enthusiasm. We hope to see more from you soon. In the meantime, explore some of the technologies our presenters used and see how they can accelerate your own research!