Each brain region contains distinct neuronal cell types with characteristic morphological, electrophysiological and molecular properties, and these different types of neurons are wired in a specific manner to form a functional circuit. A mechanistic understanding of the workings of the normal and pathological brain requires identifying all of the constituent cell types, mapping their interconnections and determining their functions.
Our laboratory focuses on two related questions regarding brain circuits:
- How many cell types are there in each brain region and how they connect each other to form a normal, functional circuit
- How stereotypical wiring principles among cell types are impacted by distinct neuropsychiatric conditions?
To this end, we developed and employ a multi-disciplinary approach that includes multi-cell patch recording (up to 12 simultaneous patching), morphological recovery, single-cell RNA sequencing, optogenetic techniques, and machine learning. Using this integrated approach, we perform large-scale, unbiased profiling of the individual neurons in brain circuit at each and every level, including their electrophysiological properties, morphology, transcriptome, and connections, in order to decipher the comprehensive blueprint of each brain circuit. We also use sophisticated mouse genetic models, in vivo whole-cell recordings, two-photon Ca2+ imaging, and behavioral assays to dissect the functional roles of each cell type in the information processings.
Based upon the canonical circuit blueprint in the normal healthy brain, we use the same approach to decipher aberrant connections between specific cell types (connectopathies) underlying distinct neuropsychiatric disorders, including epilepsy, autism spectrum disorders, and schizophrenia. Extensive research has done to probe these disorders at genetic/molecular, macro-scale, and behavior level. However, at the meso-scale level, how each neuropsychiatric condition impacts the circuit blueprint remains largely unknown. In addition, within each disorder, there are distinct etiologies that share similar symptomatology and EEG signature, raising the possibility that different etiologies induce the same circuit wiring deficits that result in the same phenotypes. Identifying the stereotypical circuit deficits for a specific type of neuropsychiatric diseases paves the way for more universal, circuit-based cell-type specific interventions for these diseases.