Investigating abnormalities in top-down cortical processing and behavior in a model of the 22q11.2 deletion

SUMMARY Schizophrenia is a neuropsychiatric disorder that causes cognitive deficits and impairments in basic sensory processing. Structural and functional imaging studies in schizophrenia patients suggest that a main structural signature of schizophrenia is reduced long-range connectivity and disconnection between brain areas, however how such reduced connectivity affects specific circuit components and cortical function remains largely unknown. In this project, we will combine in vivo linear probe recordings with optogenetic modulation in the visual system of the mouse model of 22q11 deletion syndrome to study altered bottom-up and top-down modulation of sensory processing. In addition, recent transcriptomics studies have found that neurogliaform cells, a distinct class of GABAergic inhibitory neurons, are the most affected class of neurons in schizophrenia. Neurogliaform cells primarily reside in superficial layer 1 of the cortex and receive inputs from corticocortical axons, including prefrontal cortical regions, from the thalamus and higher-order thalamic nuclei, and from subcortical neuromodulatory populations, however the in vivo function of neurogliaform cells in health and their dysfunction disease remains largely unknown due to lack of tools to specifically target them. To clarify the role of neurogliaform cells in bottom-up and top-down processing, we will manipulate activity in neurogliaform cells optogenetically in wild type and 22q11.2 mice and measure their effect on sensory processing. The research proposed in this application is conceptually innovative and significant because it will give us a better understanding of how bottom-up and top-down cortical processing and neural circuits involved in schizophrenia. This work is also technically innovative because of the novel approaches to specifically target neurogliaform cells and investigating their role in sensory processing in health and in the context of 22q11.2. Ultimately, such knowledge has the potential to offer new opportunities for identification of biomarkers of disease and for therapeutic interventions that target specific circuits.