Circuits activated by psychiatric-associated behavior: from brain-wide labeling to regional assessment using Psych-TRAP.

Background: Neuropsychiatric disorders, such as schizophrenia and autism, affect a substantial portion of the global population, 1 in 8 individuals. Genetic risk factors have been the major contribution to neuropsychiatric disorders; however, there is limited knowledge of how risk factors lead to brain circuit impairment and neuropsychiatric phenotypes. Rationale: Understanding how risk factors impact brain circuitry in the whole brain level at cellular resolution and their connection to neuropsychiatric phenotypes should help develop specific drug targets and therapeutics targeting precisely the affected cell types and circuits. Methods: We employ a clinically relevant mouse model of one of the major neuropsychiatric genetic risk factors - microdeletion in the 15q13.3 locus. Using the model, we developed a novel technique, Psych-TRAP, to label psychiatric behavior-associated circuits at whole brain level and at cellular level. We validated the genetic mouse model with clinical phenotypes and labelled transiently active cells, using TRAP2, and quantified cell densities in the whole brain using an automated pipeline, ABBA. This is the first ever approach to validate a triple transgenic mouse line with psychiatric microdeletion and understanding the cellular activation pattern and differential recruitment of cells immediately after a psychiatric-like behavior. Key findings: Further, we validated Psych-TRAP by understanding the activation of cells in already known brain areas and novel brain areas and confirmed no direct involvement of non-neuronal cells right after 3-chmabered social interaction (3-CSI). Lastly, we discovered the involvement of a dominant GABAergic component in the prefrontal cortex (PFC), mainly mediated by reelin positive (REL+) neurons and by somatostatin positive (SST+) neurons in the primary somatosensory area-trunk (SSp-tr), in mice harboring 15q13.3 microdeletion. Future implications: Thus, Psych-TRAP is a robust technique to generate mice line with disrupted copy-number variations, label transiently active cells permanently for future circuit manipulations in an unbiased manner and reveal the underlying molecular markers mediating psychiatric behaviors. This can be extended further to understand the molecular mechanisms of active cells from a particular brain area, identified from Psych-TRAP, using spatial transcriptomics and promises a potential technique for translation research targeting specific manifestations.